STAT3 inhibitors and uses thereof

ABSTRACT

Described herein, inter alia, are STAT-binding nucleic acids-including compositions and methods of using the same.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation of International Application No.PCT/US2014/066969, filed Nov. 21, 2014, which claims the benefit of U.S.Provisional Patent Application No. 61/907,953, filed Nov. 22, 2013, and62/077,035, filed Nov. 7, 2014, which are incorporated herein byreference in their entirety and for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

This invention was made with government support under grant no. CA155367awarded by the National Institutes of Health. The government has certainrights in the invention.

REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED AS AN ASCII TEXT FILE

The Sequence Listing written in file 48440-537N01US_ST25.TXT, createdMay 20, 2016, 12,425 bytes, machine format IBM-PC, MS-Windows operatingsystem, is hereby incorporated by reference.

BACKGROUND

STAT3 transcription factor, which is persistently activated in cancercells and in diverse tumor-associated immune cells, is a criticalmediator of tumorigenesis and immune evasion. As a convergence point forcytokine, growth factor and oncogenic kinase signaling, STAT3 is ahighly desirable therapeutic target. However, pharmacological inhibitionof proteins lacking enzymatic activity, such as STAT3, is challengingand requires alternative strategies. One of them is to block STAT3 DNAbinding and transcriptional activation using competitive inhibitors,such as decoy oligodeoxynucleotides (dODN). Decoy ODNs comprise thespecific, consensus sequence of the transcription factor binding site.The limiting factor in the clinical application of dODNs is difficultyin their targeted delivery, additionally complicated by the inherentsensitivity of the immune system to nucleic acids. However, immune cellsmay themselves be essential therapeutic targets in cancer therapy. Wepreviously demonstrated that ligand for the intracellular receptor TLR9(CpG ODN) allows for the delivery of oligonucleotides, such as siRNA,specifically to TLR9-positive target cells without any transfection orpackaging reagents. Disclosed herein are solutions to these and otherproblems in the art.

BRIEF SUMMARY

In an aspect is provided a compound including a TLR-binding nucleic acidsubstituent conjugated to a STAT-binding nucleic acid substituent.

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound described herein(including in an aspect, embodiment, table, figure, claim, sequencelisting, or example).

In an aspect is provided a method of treating cancer in a patient inneed of the treatment, the method including administering atherapeutically effective amount of a compound described herein(including in an aspect, embodiment, table, figure, claim, sequencelisting, or example).

In an aspect is provided a method of treating a viral disease associatedwith STAT3-dependent immunosuppression in a patient in need of thetreatment, the method including administering a compound, orpharmaceutically acceptable salt thereof, described herein (including inan aspect, embodiment, table, figure, claim, sequence listing, orexample).

In an aspect is provided a method of inhibiting the growth of a cancercell including contacting the cancer cell with a compound describedherein (including in an aspect, embodiment, table, figure, claim,sequence listing, or example).

In an aspect is provided a method of stimulating the immune system of apatient in need thereof including administering an effective amount of acompound described herein (including in an aspect, embodiment, table,figure, claim, sequence listing, or example).

In an aspect is provided a method of reducing the activity of a STATtranscription factor in a cell including contacting the cell with acompound described herein (including in an aspect, embodiment, table,figure, claim, sequence listing, or example).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1C. Design of CpG-STAT3 decoy oligodeoxynucleotide (dODN) andchemical modification for enhanced serum stability. FIG. 1A: Sequence ofthe single stranded CpG-STAT3 dODN conjugate (SEQ ID NO:6). FIG. 1B:Predicted hairpin structure of the folded CpG-STAT3 dODN (SEQ ID NO:6)with both parts of the conjugate indicated, wherein o=x (e.g. C3 carbonchain or alkylphosphate) as in FIG. 1A. FIG. 1C: Chemically-modifiedCpG-STAT3 dODN has improved resistance to degradation in human serum.

FIG. 2. CpG-STAT3 dODN conjugates but not unconjugated STAT3 dODN arequickly internalized by various target human cancer cells in vitro.

FIGS. 3A-3C. Targeted delivery of CpG-STAT3 dODN into mouse immune cellsand cancer cells in vitro. FIG. 3A: Mouse splenocytes were incubatedwith fluorescently-labeled CpG-STAT3 dODN in indicated concentrationsfor 2 h without any transfection reagents. Percentages of Cy3-positivecells pDCs (CD11c+B220+), mDCs (CD11c+B220−), macrophages (MAC;F4/80+Gr1−), B cells (B220+CD11c−), granulocytes (Gr1+F4/80−) and Tcells (CD3+) were assessed using flow cytometry. FIG. 3B: Rapidinternalization of CpG-STAT3 dODN by transformed mouse macrophages(RAW264.7) and various types of mouse cancer cells, such as M2 and B16melanoma, TC2 neuroendocrine and MB49 bladder cancer cells. FIG. 3C:CpG(A)-STAT3 dODN, with A-type CpG sequence optimized forimmunostimulation of human cells is internalized with similar efficiencyas CpG(B)-STAT3 dODN by mouse macrophages and cancer cells.

FIGS. 4A-4B. CpG-STAT3 dODN colocalized with STAT3 protein shortly afterintracellular uptake into early endosomes. Mouse RAW264.7 macrophageswere incubated with fluorescently-labeled CpG-STAT3 dODNCy3 at 500 nMconcentration for 30 min (FIG. 4A) and 120 min (FIG. B) then fixed andpermeabilized for immunostaining using antibodies specific to earlyendosome marker EEA1 (FIG. 4A) or to STAT3 (FIG. 4B) and counterstainedusing DAPi to visualize nuclei. The intracellular localization ofCpG-STAT3 dODN was analyzed using confocal microscopy.

FIG. 5. CpG-STAT3 dODN conjugates inhibit DNA binding of STAT3 in targethuman and mouse cancer cells.

FIGS. 6A-6B. CpG-STAT3 dODN induces direct cytotoxic effects in humanand mouse cancer cells in vitro. FIG. 6A: Human B cell lymphoma (Daudi),AML (MV4-11) and prostate cancer cells (DU145) were incubated with 500nM CpG(A)-STAT3 dODN for 2 days. The induction of cell death wasmeasured after Annexin V and 7AAD staining using flow cytometry. Thepercentages of early apoptotic (Annexin V+7AAD−) and late apoptotic(Annexin V+7AAD+) cells is shown. FIG. 6B: Mouse M2 melanoma andCbfb/MYH11/Mp11 AML (CMM) cells were incubated 500 nM CpG(B)-STAT3 dODNfor 2 days and analyzed as described for FIG. 6A.

FIGS. 7A-7B. Systemic CpG(A)-STAT3 dODN treatment induces regression ofdisseminated human MV4-11 leukemia in mice. NSG mice were injected i.v.with 0.5×10⁶ MV4-11luc acute myeloid leukemia cells. After 2-3 weekswhen tumors were engrafted as confirmed by Xenogen imaging, mice wereinjected daily using 5 mg/kg of CpG(A)-STAT3 dODN or negative controlCpG(A)-scrODN or left untreated. FIG. 7A: Disclosed is Xenogen imagingbefore and during treatment to detect AML regression after repeatedinjections of CpG(A)-STAT3 dODN compared to both control groups. FIG.7B: CpG(A)-STAT3 dODN treatment reduces the percentage of AML cells invarious organs including bone marrow (BM) and blood as assessed usingflow cytometry. Shown are combined results from 6 mice/group; means±SEM.

FIGS. 8A-8C. Systemic CpG-STAT3 dODN treatment induces completeregression of mouse Cbfb/MYH11/Mpl leukemia in immunocompetent mice.After 2-3 weeks when tumors were engrafted (>1%, ranging 1-5% of AMLcells in blood), mice were injected six times with CpG-Stat3 siRNA orcontrol CpG-Luciferase siRNA (5 mg/kg) every other day and euthanizedone day after last treatment. FIG. 8A: Figure depicts the effect ofCpG-STAT3 dODN treatments on spleen cellularity. Shown arerepresentative spleen sizes (left) and the measurement of spleens weight(right). FIG. 8B: Flow cytometric analysis of GFP+c-Kit⁺ AML cells inblood, bone marrows, spleens, left to right, and (FIG. 8C) thepercentage of CD8+ T cells infiltrating spleens from various groups ofmice. Shown are combined results from 6 mice/group; means±SEM.

FIG. 9. In vivo administration of CpG-STAT3dODN reducesleukemia-initiating potential of Cbfb/MYH11/Mpl AML cells

FIGS. 10A-10C. Intravenously injected CpG-STAT3dODN conjugates are moreeffective than CpG-Stat3 siRNA against disseminated leukemia in vivo.After 2-3 weeks from tumor challenge, with confirmed AML engraftment(>1%, ranging 1-5% of AML cells in blood), mice were injected iv. only 3times every other day using 5 mg/kg of CpG(B)-Stat3 siRNA,CpG(A)-STAT3dODN, CpG(B)-STAT3dODN or CpG(B)-scrambled ODN conjugatesand euthanized one day after the last treatment. Treatments using bothtypes of CpG-STAT3 dODN were more effective than CpG-Stat3 siRNA inreducing percentages of AML cells in blood (FIG. 10A), lymph nodes (FIG.10B) and bone marrow (FIG. 10C). Shown are combined results from 6mice/group; means±SEM.

FIG. 11. CpG-dODN conjugates are strongly immunostimulatory comparing tothe unconjugated decoy STAT3.

FIG. 12. CpG(A)-STAT3dODN induce potent immunostimulatory effects inhuman immune cells derived from late-stage prostate cancer patients.

FIG. 13. CpG-STAT3dODN but not the unconjugated STAT3dODN is efficientlyinternalized by bone-marrow resident leukemia cells and tumor-associatedmyeloid cells.

FIGS. 14A-14B. CpG-STAT3dODN but not the unconjugated STAT3dODN targetsperivascular macrophages in the brain. Naïve C57BL/6 mice (n=4) wereinjected with a single intravenous 5 mg/kg dose of Cy3-labeledCpG(A)-STAT3dODN, CpG(B)-STAT3dODN or STAT3dODN alone as indicated (FIG.14A-B). The uptake of fluorescently labeled oligonucleotides by totalmyeloid cells (FIG. 14A) and perivascular macrophages (FIG. 14B) wasassessed using flow cytometry in brain tissues collected at 18 hrs afterinjection.

FIGS. 15A-15C. CpG(A)-STAT3dODN is not cytotoxic for normal human immunecells. PBMCs isolated from healthy subjects were incubated in thepresence of various concentrations of CpG(A)-STAT3dODN or controlCpG(A)-scrambled ODN (FIG. 15A-C). Cells were collected after 72 h toanalyze percentages of Annexin V-positive apoptotic cells among CD3⁺ Tcells (FIG. 15A), CD19⁺ B cells (FIG. 15B) and CD303⁺ pDC (FIG. 15C)using flow cytometry. Shown are means±SEM (n=3).

FIGS. 16A-16B. Half-life of chemically modified CpG-STAT3 decoyoligodeoxynucleotides in mouse and human sera. FIGS. 16A-16B:Chemically-modified CpG-STAT3 dODN has improved resistance todegradation by serum nucleases. CpG-STAT3 dODN was incubated in 50% inmouse (FIG. 16A) or human sera (FIG. 16B) for up to 7 days, thenresolved on 7.5M Urea/15% PAGE gel and stained using ethidium bromide.FIGS. 16A-16B: Top panel—representative gel images. Bottom—graphsshowing quantification of band intensities from 3 independentexperiments; shown are means±SEM. The estimated halflife ofCpG(A)-STAT3dODN was indicated.

FIGS. 17A-17B. CpG-STAT3dODN inhibits STAT3 activity in dose-dependentmanner. FIG. 17A: Levels of STAT3 activity in human MV4-11 AML cellsincubated for 48 h with CpG-STAT3dODN in comparison to CpG-scrODN (withscrambled decoy sequence) or GpC-STAT3dODN (lacking TLR9-targetingmotif) used as negative controls. The phosphorylation of tyrosine 705 inSTAT3 (pSTAT3) in comparison to total STAT3 levels was assessed usingwestern blotting. FIG. 17B: Splenocytes were incubated with differentconcentrations of CpG-STAT3dODN for 48 h. pSTAT3 was assessed usingintracellular staining with specific antibodies and assessed using flowcytometry; means±SEM.

FIGS. 18A-18B. CpG-STAT3dODN reduces transcriptional STAT3 activity indose-dependent manner. FIGS. 18A-18B: Reporter pGL3 plasmids encodingSTAT3 responsive a2M-promoter-luciferase constructs or empty vectorswere transiently expressed MV4-11 (FIG. 18A) and KG1a (FIG. 18B) acutemyeloid leukemia cells. One day later cells were incubated for 48 h withvarious doses of CpGSTAT3dODN in comparison to CpG-scrODN orGpC-STAT3dODN used as negative controls. The level of STAT3-inducedtranscriptional activity was assessed in cell lysates by measuringluciferase activity in 3 independent experiments; means±SEM.

FIG. 19. Systemic administration of CpG-STAT3dODN reduces STAT3 activityin target TLR9-positive leukemia cells in dose-dependent manner. NSGmice were injected i.v. using MV4-11-luc AML cells. After leukemia wasestablished in various organs as confirmed by bioluminescent imaging,mice were injected intravenously using various doses of CpGSTAT3dODN orcontrol CpG-scrODN. Mice were euthanized a day later, spleens wereharvested to prepare single cell suspension and the level of STAT3activity was assessed using intracellular staining with pSTAT3-specificantibodies and flow cytometry; means±SEM (n=4).

FIGS. 20A-20D. Systemic administration of CpG-STAT3dODN inhibits STAT3signaling and induces AML regression in mice. C57BL/6 mice were injectedi.v. using Cbfb-MYH11 AML cells. After leukemia was established (1-5% ofcirculating AML cells), mice were injected 6 times every other day i.v.using 5 mg/kg of CpG-STAT3dODN or control CpG-scrODN. (FIG. 20A)CpG-STAT3dODN treatment reduces splenomegaly (FIG. 20A) and thepercentage of AML cells in spleen (FIGS. 20B-20C—top row) and bonemarrow (FIG. 20C—bottom row) as assessed using flow cytometry. Shown areresults from 4 independent experiments; means±SEM (n=5). (FIG. 20D)STAT3 inhibition results in decreased levels of STAT3 and Bcl-XLproteins expression in splenic AML cells isolated from 5 different mice.Shown are results of western blotting using β-actin for loading control.

FIGS. 21A-21C. Lack of functional immune effector cells in NSG micereduces the efficacy of CpGSTAT3dODN treatment against AML. Theimmunodeficient NSG mice were injected i.v. using Cbfb-MYH11 AML cells.After leukemia was established (1-5% of circulating AML cells), micewere injected 6 times every other day i.v. using 5 mg/kg ofCpG-STAT3dODN or control CpG-scrODN as in FIG. 20A-D. Percentages of AMLcells in blood (FIG. 21A), bone marrow (FIG. 21B) and spleens (FIG. 21C)were assessed using flow cytometry. Shown are representative dot plots(left panels) and results summary (right panel); means±SEM (n=5).

FIGS. 22A-22B. CpG-STAT3dODN treatment triggers immune activation ofboth dendritic cells (DC) and AML cells in vivo. C57BL/6 mice bearingdisseminated Cbfb-MYH11 AML were treated as in FIG. 20A-D. The level ofimmune activation was assessed in both splenic CD11c+ DCs (FIG. 22A) andAML cells (FIG. 22B) detecting surface expression of MHC class II andcostimulatory molecules such as CD40, CD80 and CD86 using flowcytometry. Shown are results from two independent experiments; means±SEM(n=5).

FIG. 23. In vivo treatment using CpG-STAT3dODN reducesleukemia-initiating potential and promotes long-term survival. C57BL/6mice were injected i.v. using the same number of Cbfb-MYH11 AML cellsisolated from donor mice treated using CpG-STAT3dODN, control CpGscrODNor PBS treated (as in FIGS. 20A-20D). The survival of recipient mice wasmonitored for 120 days as indicated. Shown are means±SEM (n=6).

FIGS. 24A-24B. Systemic administration of CpG-STAT3dODN shift thebalance between CD8 and regulatory T cells. C57BL/6 mice bearingdisseminated Cbfb-MYH11 AML were treated as in FIGS. 20A-20D. Thepercentages of CD8+ effector T cells (FIG. 24A) and CD4+/FoxP3+regulatory T cells (FIG. 24B) were assessed using flow cytometry; leftpanels—representative dot plot data; right panel—data summary. Shown areresults from two independent experiments; means±SEM (n=5).

FIGS. 25A-25F. CpG-STAT3dODN induces immunogenic effects on humanprimary AML cells from patients with recurrent leukemia. (FIG. 25A)PBMCs from AML patients' were incubated for 1 h with 250 nM ofCy3-labeled CpG-STAT3dODN conjugate or STAT3dODN alone. The uptake ofindicated oligonucleotides CFSE was assessed using flow cytometry.Left—representative dot plot; right—data summary; means±SD (n=4). (FIGS.25B-25E) CpG-STAT3 dODN inhibits STAT3 phosphorylation (FIG. 25B) andarginase expression levels (FIG. 25C), while weakly inhibiting PD-L1(FIG. 25D) and upregulating HLA-DR (FIG. 25E) in pts' AML cells asmeasured using flow cytometry; means±SD (n=5). (FIG. 25F) Blocking STAT3using CpG-dODN strategy reverses immunosuppressive effect of AML cellson T cell proliferation. CFSE dilution assay using 4:1 ration of AML toT cells; gated are proliferating T cells.

FIGS. 26A-26C. CpG-STAT3dODN alleviates immunosuppressive effects ofmyeloid-derived suppressor cells (MDSC) in vitro. (FIG. 26A) CD15+ MDSCgenerated in the presence of human prostate cancer cells (DU145) arepotently immunosuppressive. PBMCs from healthy subjects were cultured inthe presence of DU145 supernatant for 7 days and the used for autologousT cell proliferation assays in comparison with CD15− and total PBMCs.Shown are results from one of three independent assays. (FIG. 26B)CpG-STAt3dODN is quickly internalized by CD15+ MDSC in dose-dependentmanner. (FIG. 26C) CpG-STAT3dODN but not CpG-scrODN reversesimmunosuppressive effect of MDSCs on T cell proliferation as measuredusing CFSE dilution assay; means±SD (n=3).

FIG. 27. CpG-STAT3dODN: DNA-based STAT3 inhibitor.

FIGS. 28A-28B. TLR9 expression in human and mouse myeloid cells. FIG.28A) TLR9 expression at the mRNA and protein levels in the indicatedhuman immune cells (gMDSC=granulocytic myeloid-derived suppressorcells). (FIG. 28B) TLR9 expression at the mRNA and protein levels inmouse Cbfb/Myh11 acute myeloid leukemia cells.

FIG. 29. Systemic administration of CpG-STAT3dODN reduces STAT3 activityin target TLR9-positive leukemia cells in dose-dependent manner. NSGmice were injected i.v. using MV4-11-luc AML cells. After leukemia wasestablished in various organs as confirmed by bioluminescent imaging,mice were injected intravenously using various doses of CpGSTAT3dODN orcontrol CpG-scrODN. Animals were euthanized a day later, spleens wereharvested to prepare single cell suspension and the level of STAT3activity was assessed using intracellular staining with pSTAT3-specificantibodies and flow cytometry; means±SEM (n=4).

FIG. 30. “Push & Release” Strategy for leukemia immunotherapy.CpG-STAT3dODN induces immunogenic effects in normal and malignantmyeloid cells as a result of coordinated immune stimulation through TLR9triggering (“push” signal) and the elimination of negative regulation bySTAT3 (“release” signal).

DETAILED DESCRIPTION

Disclosed herein are compositions including the ligand for theintracellular receptor TLR9 (CpG ODN) and method of using the same forthe delivery of oligonucleotides, specifically to TLR9-positive targetcells without any transfection or packaging reagents. Disclosed hereinis use of this approach to deliver STAT3 decoy ODN into variety of humanand mouse target cells both in vitro and in vivo. These include normalmyeloid cells or B lymphocytes and malignant cells, such as acutemyeloid leukemia (AML), B cell lymphoma and castration-resistantprostate cancer cells. Due to extensive chemical modification(phosphothioation) of the backbone, the CpG-STAT3 dODN are highlyresistant to serum degradation with half-life exceeding 48 hrs. Thus,CpG-dODNs are suitable for systemic administration against metastaticcancers. As disclosed herein, using a disseminated model of human AML,repeated intravenous administration of CpG-STAT3 dODN results ineradication of MV4-11 leukemia within two weeks of treatment. Theantitumor efficacy of this strategy seems to be further enhanced byimmunostimulatory effect of combined TLR9-triggering and STAT3 blocking.In syngeneic mouse model of Cbfb/MYH11/Mp11 leukemia, i.v. injections ofCpG-STAT3 dODN resulted in tumor regression from bone marrow, spleen andblood within 12 days of treatment. The antitumor effect was accompaniedby immune cell activation and T cell infiltration into various organs.Thus, CpG-dODN strategy can overcome the limitations of small moleculedrugs by expanding the list of therapeutic targets to crucial yetcurrently non-druggable molecules (e.g. transcription factors).

Definitions

The abbreviations used herein have their conventional meaning within thechemical and biological arts. The chemical structures and formulae setforth herein are constructed according to the standard rules of chemicalvalency known in the chemical arts.

Where substituent groups are specified by their conventional chemicalformulae, written from left to right, they equally encompass thechemically identical substituents that would result from writing thestructure from right to left, e.g., —CH₂O— is equivalent to —OCH₂—.

The term “alkyl,” by itself or as part of another substituent, means,unless otherwise stated, a straight (i.e., unbranched) or branchednon-cyclic carbon chain (or carbon), or combination thereof, which maybe fully saturated, mono- or polyunsaturated and can include di- andmultivalent radicals, having the number of carbon atoms designated(i.e., C₁-C₁₀ means one to ten carbons). Examples of saturatedhydrocarbon radicals include, but are not limited to, groups such asmethyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl,sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example,n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkylgroup is one having one or more double bonds or triple bonds. Examplesof unsaturated alkyl groups include, but are not limited to, vinyl,2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl,3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and thehigher homologs and isomers. An alkoxy is an alkyl attached to theremainder of the molecule via an oxygen linker (—O—).

The term “alkylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkyl, asexemplified, but not limited by, —CH₂CH₂CH₂CH₂—. Typically, an alkyl (oralkylene) group will have from 1 to 24 carbon atoms, with those groupshaving 10 or fewer carbon atoms being preferred in the presentinvention. A “lower alkyl” or “lower alkylene” is a shorter chain alkylor alkylene group, generally having eight or fewer carbon atoms. Theterm “alkenylene,” by itself or as part of another substituent, means,unless otherwise stated, a divalent radical derived from an alkene.

The term “heteroalkyl,” by itself or in combination with another term,means, unless otherwise stated, a stable non-cyclic straight or branchedchain, or combinations thereof, including at least one carbon atom andat least one heteroatom selected from the group consisting of O, N, P,Si, and S, and wherein the nitrogen and sulfur atoms may optionally beoxidized, and the nitrogen heteroatom may optionally be quaternized. Theheteroatom(s) O, N, P, S, and Si may be placed at any interior positionof the heteroalkyl group or at the position at which the alkyl group isattached to the remainder of the molecule. Examples include, but are notlimited to: —CH₂—CH₂—O—CH₃, —CH₂—CH₂—NH—CH₃, —CH₂—CH₂—N(CH₃)—CH₃,—CH₂—S—CH₂—CH₃, —CH₂—CH₂, —S(O)—CH₃, —CH₂—CH₂—S(O)₂—CH₃, —CH═CH—O—CH₃,—Si(CH₃)₃, —CH₂—CH═N—OCH₃, —CH═CH—N(CH₃)—CH₃, —O—CH₃, —O—CH₂—CH₃, and—CN. Up to two or three heteroatoms may be consecutive, such as, forexample, —CH₂—NH—OCH₃ and —CH₂—O—Si(CH₃)₃.

Similarly, the term “heteroalkylene,” by itself or as part of anothersubstituent, means, unless otherwise stated, a divalent radical derivedfrom heteroalkyl, as exemplified, but not limited by,—CH₂—CH₂—S—CH₂—CH₂— and —CH₂—S—CH₂—CH₂—NH—CH₂—. For heteroalkylenegroups, heteroatoms can also occupy either or both of the chain termini(e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, andthe like). Still further, for alkylene and heteroalkylene linkinggroups, no orientation of the linking group is implied by the directionin which the formula of the linking group is written. For example, theformula —C(O)₂R′— represents both —C(O)₂R′— and —R′C(O)₂—. As describedabove, heteroalkyl groups, as used herein, include those groups that areattached to the remainder of the molecule through a heteroatom, such as—C(O)R′, —C(O)NR′, —NR′R″, —OR′, —SR′, and/or —SO₂R′. Where“heteroalkyl” is recited, followed by recitations of specificheteroalkyl groups, such as —NR′R″ or the like, it will be understoodthat the terms heteroalkyl and —NR′R″ are not redundant or mutuallyexclusive. Rather, the specific heteroalkyl groups are recited to addclarity. Thus, the term “heteroalkyl” should not be interpreted hereinas excluding specific heteroalkyl groups, such as —NR′R″ or the like.

The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or incombination with other terms, mean, unless otherwise stated, cyclicnon-aromatic versions of “alkyl” and “heteroalkyl,” respectively,wherein the carbons making up the ring or rings do not necessarily needto be bonded to a hydrogen due to all carbon valencies participating inbonds with non-hydrogen atoms. Additionally, for heterocycloalkyl, aheteroatom can occupy the position at which the heterocycle is attachedto the remainder of the molecule. Examples of cycloalkyl include, butare not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples ofheterocycloalkyl include, but are not limited to,1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl,3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl,1-piperazinyl, 2-piperazinyl, and the like. A “cycloalkylene” and a“heterocycloalkylene,” alone or as part of another substituent, means adivalent radical derived from a cycloalkyl and heterocycloalkyl,respectively.

The terms “halo” or “halogen,” by themselves or as part of anothersubstituent, mean, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom. Additionally, terms such as “haloalkyl” aremeant to include monohaloalkyl and polyhaloalkyl. For example, the term“halo(C₁-C₄)alkyl” includes, but is not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl,3-bromopropyl, and the like.

The term “acyl” means, unless otherwise stated, —C(O)R where R is asubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

The term “aryl” means, unless otherwise stated, a polyunsaturated,aromatic, hydrocarbon substituent, which can be a single ring ormultiple rings (preferably from 1 to 3 rings) that are fused together(i.e., a fused ring aryl) or linked covalently (e.g., biphenyl). A fusedring aryl refers to multiple rings fused together wherein at least oneof the fused rings is an aryl ring. The term “heteroaryl” refers to arylgroups (or rings) that contain at least one heteroatom such as N, O, orS, wherein the nitrogen and sulfur atoms are optionally oxidized, andthe nitrogen atom(s) are optionally quaternized. Thus, the term“heteroaryl” includes fused ring heteroaryl groups (i.e., multiple ringsfused together wherein at least one of the fused rings is aheteroaromatic ring). A 5,6-fused ring heteroarylene refers to two ringsfused together, wherein one ring has 5 members and the other ring has 6members, and wherein at least one ring is a heteroaryl ring. Likewise, a6,6-fused ring heteroarylene refers to two rings fused together, whereinone ring has 6 members and the other ring has 6 members, and wherein atleast one ring is a heteroaryl ring. And a 6,5-fused ring heteroarylenerefers to two rings fused together, wherein one ring has 6 members andthe other ring has 5 members, and wherein at least one ring is aheteroaryl ring. A heteroaryl group can be attached to the remainder ofthe molecule through a carbon or heteroatom. Non-limiting examples ofaryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl,4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl,2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl,2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl,5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl,4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl,3-quinolyl, and 6-quinolyl. Substituents for each of the above notedaryl and heteroaryl ring systems are selected from the group ofacceptable substituents described below. An “arylene” and a“heteroarylene,” alone or as part of another substituent, mean adivalent radical derived from an aryl and heteroaryl, respectively.Non-limiting examples of heteroaryl groups include pyridinyl,pyrimidinyl, thiophenyl, thienyl, furanyl, indolyl, benzoxadiazolyl,benzodioxolyl, benzodioxanyl, thianaphthanyl, pyrrolopyridinyl,indazolyl, quinolinyl, quinoxalinyl, pyridopyrazinyl, quinazolinonyl,benzoisoxazolyl, imidazopyridinyl, benzofuranyl, benzothienyl,benzothiophenyl, phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl,imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furylthienyl,pyridyl, pyrimidyl, benzothiazolyl, purinyl, benzimidazolyl,isoquinolyl, thiadiazolyl, oxadiazolyl, pyrrolyl, diazolyl, triazolyl,tetrazolyl, benzothiadiazolyl, isothiazolyl, pyrazolopyrimidinyl,pyrrolopyrimidinyl, benzotriazolyl, benzoxazolyl, or quinolyl. Theexamples above may be substituted or unsubstituted and divalent radicalsof each heteroaryl example above are non-limiting examples ofheteroarylene.

A fused ring heterocyloalkyl-aryl is an aryl fused to aheterocycloalkyl. A fused ring heterocycloalkyl-heteroaryl is aheteroaryl fused to a heterocycloalkyl. A fused ringheterocycloalkyl-cycloalkyl is a heterocycloalkyl fused to a cycloalkyl.A fused ring heterocycloalkyl-heterocycloalkyl is a heterocycloalkylfused to another heterocycloalkyl. Fused ring heterocycloalkyl-aryl,fused ring heterocycloalkyl-heteroaryl, fused ringheterocycloalkyl-cycloalkyl, or fused ringheterocycloalkyl-heterocycloalkyl may each independently beunsubstituted or substituted with one or more of the substitutentsdescribed herein.

The term “oxo,” as used herein, means an oxygen that is double bonded toa carbon atom.

The term “alkylsulfonyl,” as used herein, means a moiety having theformula —S(O₂)—R′, where R′ is a substituted or unsubstituted alkylgroup as defined above. R′ may have a specified number of carbons (e.g.,“C₁-C₄ alkylsulfonyl”).

Each of the above terms (e.g., “alkyl,” “heteroalkyl,” “aryl,” and“heteroaryl”) includes both substituted and unsubstituted forms of theindicated radical. Preferred substituents for each type of radical areprovided below.

Substituents for the alkyl and heteroalkyl radicals (including thosegroups often referred to as alkylene, alkenyl, heteroalkylene,heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, andheterocycloalkenyl) can be one or more of a variety of groups selectedfrom, but not limited to, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′,-halogen, —SiR′R″R′″, —OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC(O)NR′R″,—NR″C(O)R′, —NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″−,—NR—C(NR′R″)═NR′″, —S(O)₂R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′,—NR′NR″R′″, —ONR′R″, —NR′C═(O)NR″NR′″R″″, —CN, —NO₂, in a number rangingfrom zero to (2m′+1), where m′ is the total number of carbon atoms insuch radical. R, R′, R″, R′″, and R″″ each preferably independentlyrefer to hydrogen, substituted or unsubstituted heteroalkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstitutedheterocycloalkyl, substituted or unsubstituted aryl (e.g., arylsubstituted with 1-3 halogens), substituted or unsubstituted heteroaryl,substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, orarylalkyl groups. When a compound of the invention includes more thanone R group, for example, each of the R groups is independently selectedas are each R′, R″, R′″, and R″″ group when more than one of thesegroups is present. When R′ and R″ are attached to the same nitrogenatom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-,or 7-membered ring. For example, —NR′R″ includes, but is not limited to,1-pyrrolidinyl and 4-morpholinyl. From the above discussion ofsubstituents, one of skill in the art will understand that the term“alkyl” is meant to include groups including carbon atoms bound togroups other than hydrogen groups, such as haloalkyl (e.g., —CF₃ and—CH₂CF₃) and acyl (e.g., —C(O)CH₃, —C(O)CF₃, —C(O)CH₂OCH₃, and thelike).

Similar to the substituents described for the alkyl radical,substituents for the aryl and heteroaryl groups are varied and areselected from, for example: —OR′, —NR′R″, —SR′, -halogen, —SiR′R″R′″,—OC(O)R′, —C(O)R′, —CO₂R′, —CONR′R″, —OC (O)NR′R″, —NR″C(O)R′,—NR′—C(O)NR″R′″, —NR″C(O)₂R′, —NR—C(NR′R″R′″)═NR″″, —NR—C(NR′ R″)═NR′″,—S(O)R′, —S(O)₂R′, —S(O)₂NR′R″, —NRSO₂R′, —NR′NR″R′″, —ONR′R″,—NR′C═(O)NR″NR′″R″″, —CN, —NO₂, —R′, —N₃, —CH(Ph)₂, fluoro(C₁-C₄)alkoxy,and fluoro(C₁-C₄)alkyl, in a number ranging from zero to the totalnumber of open valences on the aromatic ring system; and where R′, R″,R′″, and R″″ are preferably independently selected from hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, andsubstituted or unsubstituted heteroaryl. When a compound of theinvention includes more than one R group, for example, each of the Rgroups is independently selected as are each R′, R″, R′″, and R″″ groupswhen more than one of these groups is present.

Two or more substituents may optionally be joined to form aryl,heteroaryl, cycloalkyl, or heterocycloalkyl groups. Such so-calledring-forming substituents are typically, though not necessarily, foundattached to a cyclic base structure. In one embodiment, the ring-formingsubstituents are attached to adjacent members of the base structure. Forexample, two ring-forming substituents attached to adjacent members of acyclic base structure create a fused ring structure. In anotherembodiment, the ring-forming substituents are attached to a singlemember of the base structure. For example, two ring-forming substituentsattached to a single member of a cyclic base structure create aspirocyclic structure. In yet another embodiment, the ring-formingsubstituents are attached to non-adjacent members of the base structure.

Two of the substituents on adjacent atoms of the aryl or heteroaryl ringmay optionally form a ring of the formula -T-C(O)—(CRR′)_(q)—U—, whereinT and U are independently —NR—, —O—, —CRR′—, or a single bond, and q isan integer of from 0 to 3. Alternatively, two of the substituents onadjacent atoms of the aryl or heteroaryl ring may optionally be replacedwith a substituent of the formula -A-(CH₂)_(r)—B—, wherein A and B areindependently —CRR′—, —O—, —NR—, —S—, —S(O)—, —S(O)₂—, —S(O)₂NR′—, or asingle bond, and r is an integer of from 1 to 4. One of the single bondsof the new ring so formed may optionally be replaced with a double bond.Alternatively, two of the substituents on adjacent atoms of the aryl orheteroaryl ring may optionally be replaced with a substituent of theformula —(CRR′)_(s)—X′—(C″R″R′″)_(d)—, where s and d are independentlyintegers of from 0 to 3, and X′ is —O—, —NR′—, —S—, —S(O)—, —S(O)₂—, or—S(O)₂NR′—. The substituents R, R′, R″, and R′″ are preferablyindependently selected from hydrogen, substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, and substituted or unsubstitutedheteroaryl.

As used herein, the terms “heteroatom” or “ring heteroatom” are meant toinclude, oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), andsilicon (Si).

A “substituent group,” as used herein, means a group selected from thefollowing moieties:

-   -   (A) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,        —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,        —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,        —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃, unsubstituted alkyl,        unsubstituted heteroalkyl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, unsubstituted aryl,        unsubstituted heteroaryl, and    -   (B) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,        heteroaryl, substituted with at least one substituent selected        from:        -   (i) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂,            —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,            —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH,            —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃, unsubstituted alkyl,            unsubstituted heteroalkyl, unsubstituted cycloalkyl,            unsubstituted heterocycloalkyl, unsubstituted aryl,            unsubstituted heteroaryl, and        -   (ii) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl,            heteroaryl, substituted with at least one substituent            selected from:            -   (a) oxo, halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂,                —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl, and            -   (b) alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl,                aryl, heteroaryl, substituted with at least one                substituent selected from: oxo,            -   halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH,                —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,                —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H,                —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, —NHSO₂CH₃, —N₃,                unsubstituted alkyl, unsubstituted heteroalkyl,                unsubstituted cycloalkyl, unsubstituted                heterocycloalkyl, unsubstituted aryl, unsubstituted                heteroaryl.

A “size-limited substituent” or “size-limited substituent group,” asused herein, means a group selected from all of the substituentsdescribed above for a “substituent group,” wherein each substituted orunsubstituted alkyl is a substituted or unsubstituted C₁-C₂₀ alkyl, eachsubstituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl.

A “lower substituent” or “lower substituent group,” as used herein,means a group selected from all of the substituents described above fora “substituent group,” wherein each substituted or unsubstituted alkylis a substituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl.

In some embodiments, each substituted group described in the compoundsherein is substituted with at least one substituent group. Morespecifically, in some embodiments, each substituted alkyl, substitutedheteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl,substituted aryl, substituted heteroaryl, substituted alkylene,substituted heteroalkylene, substituted cycloalkylene, substitutedheterocycloalkylene, substituted arylene, and/or substitutedheteroarylene described in the compounds herein are substituted with atleast one substituent group. In other embodiments, at least one or allof these groups are substituted with at least one size-limitedsubstituent group. In other embodiments, at least one or all of thesegroups are substituted with at least one lower substituent group.

In other embodiments of the compounds herein, each substituted orunsubstituted alkyl may be a substituted or unsubstituted C₁-C₂₀ alkyl,each substituted or unsubstituted heteroalkyl is a substituted orunsubstituted 2 to 20 membered heteroalkyl, each substituted orunsubstituted cycloalkyl is a substituted or unsubstituted C₃-C₈cycloalkyl, each substituted or unsubstituted heterocycloalkyl is asubstituted or unsubstituted 3 to 8 membered heterocycloalkyl, eachsubstituted or unsubstituted aryl is a substituted or unsubstitutedC₆-C₁₀ aryl, and/or each substituted or unsubstituted heteroaryl is asubstituted or unsubstituted 5 to 10 membered heteroaryl. In someembodiments of the compounds herein, each substituted or unsubstitutedalkylene is a substituted or unsubstituted C₁-C₂₀ alkylene, eachsubstituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 20 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₈cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 8 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 10 membered heteroarylene.

In some embodiments, each substituted or unsubstituted alkyl is asubstituted or unsubstituted C₁-C₈ alkyl, each substituted orunsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8membered heteroalkyl, each substituted or unsubstituted cycloalkyl is asubstituted or unsubstituted C₃-C₇ cycloalkyl, each substituted orunsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7membered heterocycloalkyl, each substituted or unsubstituted aryl is asubstituted or unsubstituted C₆-C₁₀ aryl, and/or each substituted orunsubstituted heteroaryl is a substituted or unsubstituted 5 to 9membered heteroaryl. In some embodiments, each substituted orunsubstituted alkylene is a substituted or unsubstituted C₁-C₈ alkylene,each substituted or unsubstituted heteroalkylene is a substituted orunsubstituted 2 to 8 membered heteroalkylene, each substituted orunsubstituted cycloalkylene is a substituted or unsubstituted C₃-C₇cycloalkylene, each substituted or unsubstituted heterocycloalkylene isa substituted or unsubstituted 3 to 7 membered heterocycloalkylene, eachsubstituted or unsubstituted arylene is a substituted or unsubstitutedC₆-C₁₀ arylene, and/or each substituted or unsubstituted heteroaryleneis a substituted or unsubstituted 5 to 9 membered heteroarylene. In someembodiments, the compound is a chemical species set forth in theExamples section below.

The term “pharmaceutically acceptable salts” is meant to include saltsof the active compounds that are prepared with relatively nontoxic acidsor bases, depending on the particular substituents found on thecompounds described herein. When compounds of the present inventioncontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable base additionsalts include sodium, potassium, calcium, ammonium, organic amino, ormagnesium salt, or a similar salt. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,monohydrogenphosphoric, dihydrogenphosphoric, sulfuric,monohydrogensulfuric, hydriodic, or phosphorous acids and the like, aswell as the salts derived from relatively nontoxic organic acids likeacetic, propionic, isobutyric, maleic, malonic, benzoic, succinic,suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic,p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Alsoincluded are salts of amino acids such as arginate and the like, andsalts of organic acids like glucuronic or galactunoric acids and thelike (see, e.g., Berge et al., Journal of Pharmaceutical Science 66:1-19(1977)). Certain specific compounds of the present invention containboth basic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts. Otherpharmaceutically acceptable carriers known to those of skill in the artare suitable for the present invention. Salts tend to be more soluble inaqueous or other protonic solvents that are the corresponding free baseforms. In other cases, the preparation may be a lyophilized powder in 1mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5to 5.5, that is combined with buffer prior to use.

Thus, the compounds of the present invention may exist as salts, such aswith pharmaceutically acceptable acids. The present invention includessuch salts. Examples of such salts include hydrochlorides,hydrobromides, sulfates, methanesulfonates, nitrates, maleates,acetates, citrates, fumarates, tartrates (e.g., (+)-tartrates,(−)-tartrates, or mixtures thereof including racemic mixtures),succinates, benzoates, and salts with amino acids such as glutamic acid.These salts may be prepared by methods known to those skilled in theart.

The neutral forms of the compounds are preferably regenerated bycontacting the salt with a base or acid and isolating the parentcompound in the conventional manner. The parent form of the compounddiffers from the various salt forms in certain physical properties, suchas solubility in polar solvents.

In addition to salt forms, the present invention provides compounds,which are in a prodrug form. Prodrugs of the compounds described hereinare those compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous forms.In general, all physical forms are equivalent for the uses contemplatedby the present invention and are intended to be within the scope of thepresent invention.

As used herein, the term “salt” refers to acid or base salts of thecompounds used in the methods of the present invention. Illustrativeexamples of acceptable salts are mineral acid (hydrochloric acid,hydrobromic acid, phosphoric acid, and the like) salts, organic acid(acetic acid, propionic acid, glutamic acid, citric acid and the like)salts, quaternary ammonium (methyl iodide, ethyl iodide, and the like)salts.

Certain compounds of the present invention possess asymmetric carbonatoms (optical or chiral centers) or double bonds; the enantiomers,racemates, diastereomers, tautomers, geometric isomers, stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers areencompassed within the scope of the present invention. The compounds ofthe present invention do not include those which are known in art to betoo unstable to synthesize and/or isolate. The present invention ismeant to include compounds in racemic and optically pure forms.Optically active (R)- and (S)-, or (D)- and (L)-isomers may be preparedusing chiral synthons or chiral reagents, or resolved using conventionaltechniques. When the compounds described herein contain olefinic bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

As used herein, the term “isomers” refers to compounds having the samenumber and kind of atoms, and hence the same molecular weight, butdiffering in respect to the structural arrangement or configuration ofthe atoms.

The term “tautomer,” as used herein, refers to one of two or morestructural isomers which exist in equilibrium and which are readilyconverted from one isomeric form to another.

It will be apparent to one skilled in the art that certain compounds ofthis invention may exist in tautomeric forms, all such tautomeric formsof the compounds being within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude all stereochemical forms of the structure; i.e., the R and Sconfigurations for each asymmetric center. Therefore, singlestereochemical isomers as well as enantiomeric and diastereomericmixtures of the present compounds are within the scope of the invention.

Unless otherwise stated, structures depicted herein are also meant toinclude compounds which differ only in the presence of one or moreisotopically enriched atoms. For example, compounds having the presentstructures except for the replacement of a hydrogen by a deuterium ortritium, or the replacement of a carbon by ¹³C- or ¹⁴C-enriched carbonare within the scope of this invention.

The compounds of the present invention may also contain unnaturalproportions of atomic isotopes at one or more of the atoms thatconstitute such compounds. For example, the compounds may beradiolabeled with radioactive isotopes, such as for example tritium(³H), iodine-125 (¹²⁵I), or carbon-14 (¹⁴C). All isotopic variations ofthe compounds of the present invention, whether radioactive or not, areencompassed within the scope of the present invention.

The symbol “

” denotes the point of attachment of a chemical moiety to the remainderof a molecule or chemical formula.

The terms “a” or “an,” as used in herein means one or more. In addition,the phrase “substituted with a[n],” as used herein, means the specifiedgroup may be substituted with one or more of any or all of the namedsubstituents. For example, where a group, such as an alkyl or heteroarylgroup, is “substituted with an unsubstituted C₁-C₂₀ alkyl, orunsubstituted 2 to 20 membered heteroalkyl,” the group may contain oneor more unsubstituted C₁-C₂₀ alkyls, and/or one or more unsubstituted 2to 20 membered heteroalkyls. Moreover, where a moiety is substitutedwith an R substituent, the group may be referred to as “R-substituted.”Where a moiety is R-substituted, the moiety is substituted with at leastone R substituent and each R substituent is optionally different.

Descriptions of compounds of the present invention are limited byprinciples of chemical bonding known to those skilled in the art.Accordingly, where a group may be substituted by one or more of a numberof substituents, such substitutions are selected so as to comply withprinciples of chemical bonding and to give compounds which are notinherently unstable and/or would be known to one of ordinary skill inthe art as likely to be unstable under ambient conditions, such asaqueous, neutral, and several known physiological conditions. Forexample, a heterocycloalkyl or heteroaryl is attached to the remainderof the molecule via a ring heteroatom in compliance with principles ofchemical bonding known to those skilled in the art thereby avoidinginherently unstable compounds.

The terms “treating” or “treatment” refers to any indicia of success inthe treatment or amelioration of an injury, disease, pathology orcondition, including any objective or subjective parameter such asabatement; remission; diminishing of symptoms or making the injury,pathology or condition more tolerable to the patient; slowing in therate of degeneration or decline; making the final point of degenerationless debilitating; improving a patient's physical or mental well-being.The treatment or amelioration of symptoms can be based on objective orsubjective parameters; including the results of a physical examination,neuropsychiatric exams, and/or a psychiatric evaluation. For example,certain methods herein treat cancer (e.g. prostate cancer,castration-resistant prostate cancer, breast cancer, triple negativebreast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cellcarcinoma (e.g head, neck, or esophagus), colorectal cancer, leukemia,acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma).For example certain methods herein treat cancer by decreasing orreducing or preventing the occurrence, growth, metastasis, orprogression of cancer; or treat cancer by decreasing a symptom ofcancer. Symptoms of cancer (e.g. prostate cancer, castration-resistantprostate cancer, breast cancer, triple negative breast cancer,glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.ghead, neck, or esophagus), colorectal cancer, leukemia, acute myeloidleukemia, lymphoma, B cell lymphoma, or multiple myeloma) would be knownor may be determined by a person of ordinary skill in the art. The term“treating” and conjugations thereof, include prevention of an injury,pathology, condition, or disease (e.g. preventing the development of oneor more symptoms of cancer (e.g. prostate cancer, castration-resistantprostate cancer, breast cancer, triple negative breast cancer,glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.ghead, neck, or esophagus), colorectal cancer, leukemia, acute myeloidleukemia, lymphoma, B cell lymphoma, or multiple myeloma)). For examplecertain methods herein treat viral disease (e.g. herpesvirus infectionassociated disease or hepatitis virus infection associated disease orHIV infection associated disease) by decreasing or reducing orpreventing the occurrence, growth, or progression of the virus infectionor virus; or treat viral disease (e.g. herpesvirus infection associateddisease or hepatitis virus infection associated disease or HIV infectionassociated disease) by decreasing a symptom of viral disease (e.g.herpesvirus infection associated disease or hepatitis virus infectionassociated disease or HIV infection associated disease).

An “effective amount” is an amount sufficient to accomplish a statedpurpose (e.g. achieve the effect for which it is administered, treat adisease, reduce enzyme activity, increase enzyme activity, reducetranscriptional activity, increase transcriptional activity, reduce oneor more symptoms of a disease or condition). An example of an “effectiveamount” is an amount sufficient to contribute to the treatment,prevention, or reduction of a symptom or symptoms of a disease, whichcould also be referred to as a “therapeutically effective amount.” A“reduction” of a symptom or symptoms (and grammatical equivalents ofthis phrase) means decreasing of the severity or frequency of thesymptom(s), or elimination of the symptom(s). A “prophylacticallyeffective amount” of a drug is an amount of a drug that, whenadministered to a subject, will have the intended prophylactic effect,e.g., preventing or delaying the onset (or reoccurrence) of an injury,disease, pathology or condition, or reducing the likelihood of the onset(or reoccurrence) of an injury, disease, pathology, or condition, ortheir symptoms. The full prophylactic effect does not necessarily occurby administration of one dose, and may occur only after administrationof a series of doses. Thus, a prophylactically effective amount may beadministered in one or more administrations. An “activity decreasingamount,” as used herein, refers to an amount of antagonist (inhibitor)required to decrease the activity of an enzyme or protein (e.g.transcription factor) relative to the absence of the antagonist. An“activity increasing amount,” as used herein, refers to an amount ofagonist (activator) required to increase the activity of an enzyme orprotein (e.g. transcription factor) relative to the absence of theagonist. A “function disrupting amount,” as used herein, refers to theamount of antagonist (inhibitor) required to disrupt the function of anenzyme or protein (e.g. transcription factor) relative to the absence ofthe antagonist. A “function increasing amount,” as used herein, refersto the amount of agonist (activator) required to increase the functionof an enzyme or protein (e.g. transcription factor) relative to theabsence of the agonist. The exact amounts will depend on the purpose ofthe treatment, and will be ascertainable by one skilled in the art usingknown techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms(vols. 1-3, 1992); Lloyd, The Art, Science and Technology ofPharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999);and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003,Gennaro, Ed., Lippincott, Williams & Wilkins).

The term “associated” or “associated with” in the context of a substanceor substance activity or function associated with a disease (e.g cancer(e.g. prostate cancer, castration-resistant prostate cancer, breastcancer, triple negative breast cancer, glioblastoma, ovarian cancer,lung cancer, squamous cell carcinoma (e.g head, neck, or esophagus),colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B celllymphoma, or multiple myeloma)) means that the disease (e.g. cancer(e.g. prostate cancer, castration-resistant prostate cancer, breastcancer, triple negative breast cancer, glioblastoma, ovarian cancer,lung cancer, squamous cell carcinoma (e.g head, neck, or esophagus),colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B celllymphoma, or multiple myeloma) or viral disease (e.g. herpesvirusinfection associated disease or hepatitis virus infection associateddisease or HIV infection associated disease)) is caused by (in whole orin part), or a symptom of the disease is caused by (in whole or in part)the substance or substance activity or function. For example, a symptomof a disease or condition associated with an increase in STAT3 activitymay be a symptom that results (entirely or partially) from an increasein STAT3 activity (e.g increase in STAT3 transcriptional activation,increase in STAT3 activation of a signal transduction or signallingpathway). As used herein, what is described as being associated with adisease, if a causative agent, could be a target for treatment of thedisease. For example, a disease associated with increased STAT3 activity(e.g increase in STAT3 transcriptional activation, increase in STAT3activation of a signal transduction or signalling pathway), may betreated with an agent (e.g. compound as described herein) effective fordecreasing the level of activity of STAT3 or STAT3 pathway. For example,a disease associated with STAT3, may be treated with an agent (e.g.compound as described herein) effective for decreasing the level ofactivity of STAT3 or a downstream component or effector of STAT3. Forexample, a symptom of a disease or condition associated with an increasein STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)activity may be a symptom that results (entirely or partially) from anincrease in STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6) activity (e.g increase in STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) transcriptional activation, increase in STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activationof a signal transduction or signalling pathway). As used herein, what isdescribed as being associated with a disease, if a causative agent,could be a target for treatment of the disease. For example, a diseaseassociated with increased STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) activity (e.g increase in STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) transcriptional activation,increase in STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6) activation of a signal transduction or signalling pathway), maybe treated with an agent (e.g. compound as described herein) effectivefor decreasing the level of activity of a STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) or a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) pathway. For example, a disease associated with a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) may be treated with an agent (e.g. compound as describedherein) effective for decreasing the level of activity of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) or a downstream component or effector of a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6).

“Control” or “control experiment” is used in accordance with its plainordinary meaning and refers to an experiment in which the subjects orreagents of the experiment are treated as in a parallel experimentexcept for omission of a procedure, reagent, or variable of theexperiment. In some instances, the control is used as a standard ofcomparison in evaluating experimental effects.

“Contacting” is used in accordance with its plain ordinary meaning andrefers to the process of allowing at least two distinct species (e.g.chemical compounds including biomolecules, or cells) to becomesufficiently proximal to react, interact or physically touch. It shouldbe appreciated, however, that the resulting reaction product can beproduced directly from a reaction between the added reagents or from anintermediate from one or more of the added reagents which can beproduced in the reaction mixture. The term “contacting” may includeallowing two species to react, interact, or physically touch, whereinthe two species may be a compound as described herein and a protein orenzyme (e.g. a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6)). In some embodiments contactingincludes allowing a compound described herein to interact with a proteinor enzyme that is involved in a signaling pathway (e.g. a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) pathway).

As defined herein, the term “inhibition”, “inhibit”, “inhibiting” andthe like in reference to a protein-inhibitor (e.g. antagonist)interaction means negatively affecting (e.g. decreasing) the activity orfunction of the protein relative to the activity or function of theprotein in the absence of the inhibitor. In some embodiments inhibitionrefers to reduction of a disease or symptoms of disease. In someembodiments, inhibition refers to a reduction in the activity of asignal transduction pathway or signaling pathway. Thus, inhibitionincludes, at least in part, partially or totally blocking stimulation,decreasing, preventing, or delaying activation, or inactivating,desensitizing, or down-regulating signal transduction or enzymaticactivity or the amount of a protein. In some embodiments, inhibitionrefers to a decrease in the activity of a signal transduction pathway orsignaling pathway (e.g. a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) activated pathway). Thus,inhibition may include, at least in part, partially or totallydecreasing stimulation, decreasing or reducing activation, orinactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein increased in a disease(e.g. level of a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) activity or protein or level oractivity of a component of a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway, wherein each isassociated with cancer (e.g. prostate cancer, castration-resistantprostate cancer, breast cancer, triple negative breast cancer,glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.ghead, neck, or esophagus), colorectal cancer, leukemia, acute myeloidleukemia, lymphoma, B cell lymphoma, or multiple myeloma)) or a viraldisease (e.g. herpesvirus infection associated disease or hepatitisvirus infection associated disease or HIV infection associated disease).Inhibition may include, at least in part, partially or totallydecreasing stimulation, decreasing or reducing activation, ordeactivating, desensitizing, or down-regulating signal transduction orenzymatic activity or the amount of a protein (e.g. a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6),protein downstream in a pathway from a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6), proteindownstream in a pathway activated by a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)) that may modulatethe level of another protein or increase cell survival (e.g. a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) pathway activity may increase cell survival in cells that mayor may not have an increase in a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway activity relativeto a non-disease control or decrease in a STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathwayactivity may increase cell survival in cells that may or may not have adecrease in a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) pathway activity relative to anon-disease control). In embodiments, the activity or function of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) that is inhibited is STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) transcriptional activation. In embodiments,the activity or function of a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) that is inhibited is STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)transcriptional inhibition. In embodiments, the activity or function ofa STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) that is inhibited is STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) binding to genomicDNA. In embodiments, the activity or function of a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) thatis inhibited is STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) binding to a STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) binding site in genomic DNA.

As defined herein, the term “activation”, “activate”, “activating” andthe like in reference to a protein-activator (e.g. agonist) interactionmeans positively affecting (e.g. increasing) the activity or function ofthe protein (e.g. a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6), component of a pathway including aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6), or component of a pathway including a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6)) relative to the activity or function of the protein in theabsence of the activator (e.g. compound described herein). In someembodiments, activation refers to an increase in the activity of asignal transduction pathway or signaling pathway (e.g. a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) pathway). Thus, activation may include, at least in part,partially or totally increasing stimulation, increasing or enablingactivation, or activating, sensitizing, or up-regulating signaltransduction or enzymatic activity or the amount of a protein decreasedin a disease (e.g. level of STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) activity or level of protein or activitydecreased by a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) or protein associated with cancer (e.g.prostate cancer, castration-resistant prostate cancer, breast cancer,triple negative breast cancer, glioblastoma, ovarian cancer, lungcancer, squamous cell carcinoma (e.g head, neck, or esophagus),colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B celllymphoma, or multiple myeloma) or viral disease (e.g. herpesvirusinfection associated disease or hepatitis virus infection associateddisease or HIV infection associated disease)). Activation may include,at least in part, partially or totally increasing stimulation,increasing or enabling activation, or activating, sensitizing, orup-regulating signal transduction or enzymatic activity or the amount ofa protein (e.g. a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6), protein downstream of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6), protein activated or upregulated by a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)) thatmay modulate the level of another protein or increase cell survival(e.g. increase in a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) activity may increase cell survival incells that may or may not have an increase in a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)activity relative to a non-disease control).

The term “modulator” refers to a composition that increases or decreasesthe level of a target molecule or the function of a target molecule(e.g. a STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) transcriptional activation or a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) binding to genomic DNA, or a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) binding to a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) binding site on DNA). In some embodiments, a modulator of aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) or a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway is a compound thatreduces the severity of one or more symptoms of a disease associatedwith a STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) or a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway (e.g. diseaseassociated with an increase in the level of a STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity orprotein or a STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) pathway activity or protein, for examplecancer (e.g. prostate cancer, castration-resistant prostate cancer,breast cancer, triple negative breast cancer, glioblastoma, ovariancancer, lung cancer, squamous cell carcinoma (e.g head, neck, oresophagus), colorectal cancer, leukemia, acute myeloid leukemia,lymphoma, B cell lymphoma, or multiple myeloma) or viral disease (e.g.herpesvirus infection associated disease or hepatitis virus infectionassociated disease or HIV infection associated disease)) or a diseasethat is not caused by a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) or a STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway butmay benefit from modulation of a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) or a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)pathway activity (e.g. decreasing in level or level of activity of aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) or a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway). In embodiments, amodulator of a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) or a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) pathway is ananti-cancer agent. In embodiments, a modulator of a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) or aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) pathway is an anti-viral agent.

“Patient” or “subject in need thereof” refers to a living organismsuffering from or prone to a disease or condition that can be treated byadministration of a compound or pharmaceutical composition, as providedherein. Non-limiting examples include humans, other mammals, bovines,rats, mice, dogs, monkeys, goat, sheep, cows, deer, and othernon-mammalian animals. In some embodiments, a patient is human. In someembodiments, a patient is a mammal. In some embodiments, a patient is amouse. In some embodiments, a patient is an experimental animal. In someembodiments, a patient is a rat. In some embodiments, a patient is atest animal.

“Disease” or “condition” refer to a state of being or health status of apatient or subject capable of being treated with a compound,pharmaceutical composition, or method provided herein. In someembodiments, the disease is a disease related to (e.g. caused by) anincrease in the level of a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6), STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) phosphorylation, or a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) pathway activity, or pathway activated by a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). Insome embodiments, the disease is cancer (e.g. prostate cancer,castration-resistant prostate cancer, breast cancer, triple negativebreast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cellcarcinoma (e.g head, neck, or esophagus), colorectal cancer, leukemia,acute myeloid leukemia, lymphoma, B cell lymphoma, or multiple myeloma).In embodiments, the disease is a viral disease (e.g. herpesvirusinfection associated disease or hepatitis virus infection associateddisease or HIV infection associated disease) associated withSTAT3-dependent immunosuppression.

Examples of diseases, disorders, or conditions include, but are notlimited to, cancer (e.g. prostate cancer, castration-resistant prostatecancer, breast cancer, triple negative breast cancer, glioblastoma,ovarian cancer, lung cancer, squamous cell carcinoma (e.g head, neck, oresophagus), colorectal cancer, leukemia, acute myeloid leukemia,lymphoma, B cell lymphoma, or multiple myeloma). In some instances,“disease” or “condition” refers to cancer. In some further instances,“cancer” refers to human cancers and carcinomas, sarcomas,adenocarcinomas, lymphomas, leukemias, melanomas, etc., including solidand lymphoid cancers, kidney, breast, lung, bladder, colon, ovarian,prostate, pancreas, stomach, brain, head and neck, skin, uterine,testicular, glioma, esophagus, liver cancer, including hepatocarcinoma,lymphoma, including B-acute lymphoblastic lymphoma, non-Hodgkin'slymphomas (e.g., Burkitt's, Small Cell, and Large Cell lymphomas),Hodgkin's lymphoma, leukemia (including AML, ALL, and CML), and/ormultiple myeloma. In some further instances, “cancer” refers to lungcancer, breast cancer, ovarian cancer, leukemia, lymphoma, melanoma,pancreatic cancer, sarcoma, bladder cancer, bone cancer, brain cancer,cervical cancer, colon cancer, esophageal cancer, gastric cancer, livercancer, head and neck cancer, kidney cancer, myeloma, thyroid cancer,prostate cancer, metastatic cancer, or carcinoma.

As used herein, the term “cancer” refers to all types of cancer,neoplasm or malignant tumors found in mammals, including leukemia,lymphoma, carcinomas and sarcomas. Exemplary cancers that may be treatedwith a compound, pharmaceutical composition, or method provided hereininclude lymphoma, sarcoma, bladder cancer, bone cancer, brain tumor,cervical cancer, colon cancer, esophageal cancer, gastric cancer, headand neck cancer, kidney cancer, myeloma, thyroid cancer, leukemia,prostate cancer, breast cancer (e.g. triple negative, ER positive, ERnegative, chemotherapy resistant, herceptin resistant, HER2 positive,doxorubicin resistant, tamoxifen resistant, ductal carcinoma, lobularcarcinoma, primary, metastatic), ovarian cancer, pancreatic cancer,liver cancer (e.g. hepatocellular carcinoma), lung cancer (e.g.non-small cell lung carcinoma, squamous cell lung carcinoma,adenocarcinoma, large cell lung carcinoma, small cell lung carcinoma,carcinoid, sarcoma), glioblastoma multiforme, glioma, melanoma, prostatecancer, castration-resistant prostate cancer, breast cancer, triplenegative breast cancer, glioblastoma, ovarian cancer, lung cancer,squamous cell carcinoma (e.g head, neck, or esophagus), colorectalcancer, leukemia, acute myeloid leukemia, lymphoma, B cell lymphoma, ormultiple myeloma. Additional examples include, cancer of the thyroid,endocrine system, brain, breast, cervix, colon, head & neck, esophagus,liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary,sarcoma, stomach, uterus or Medulloblastoma, Hodgkin's Disease,Non-Hodgkin's Lymphoma, multiple myeloma, neuroblastoma, glioma,glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primarythrombocytosis, primary macroglobulinemia, primary brain tumors, cancer,malignant pancreatic insulinoma, malignant carcinoid, urinary bladdercancer, premalignant skin lesions, testicular cancer, lymphomas, thyroidcancer, neuroblastoma, esophageal cancer, genitourinary tract cancer,malignant hypercalcemia, endometrial cancer, adrenal cortical cancer,neoplasms of the endocrine or exocrine pancreas, medullary thyroidcancer, medullary thyroid carcinoma, melanoma, colorectal cancer,papillary thyroid cancer, hepatocellular carcinoma, Paget's Disease ofthe Nipple, Phyllodes Tumors, Lobular Carcinoma, Ductal Carcinoma,cancer of the pancreatic stellate cells, cancer of the hepatic stellatecells, or prostate cancer.

The term “leukemia” refers broadly to progressive, malignant diseases ofthe blood-forming organs and is generally characterized by a distortedproliferation and development of leukocytes and their precursors in theblood and bone marrow. Leukemia is generally clinically classified onthe basis of (1) the duration and character of the disease-acute orchronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid(lymphogenous), or monocytic; and (3) the increase or non-increase inthe number abnormal cells in the blood-leukemic or aleukemic(subleukemic). Exemplary leukemias that may be treated with a compound,pharmaceutical composition, or method provided herein include, forexample, acute nonlymphocytic leukemia, chronic lymphocytic leukemia,acute granulocytic leukemia, chronic granulocytic leukemia, acutepromyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, aleukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovineleukemia, chronic myelocytic leukemia, leukemia cutis, embryonalleukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia,hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia,stem cell leukemia, acute monocytic leukemia, leukopenic leukemia,lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia,lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia,mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia,monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloidgranulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasmacell leukemia, multiple myeloma, plasmacytic leukemia, promyelocyticleukemia, Rieder cell leukemia, Schilling's leukemia, stem cellleukemia, subleukemic leukemia, or undifferentiated cell leukemia.

The term “sarcoma” generally refers to a tumor which is made up of asubstance like the embryonic connective tissue and is generally composedof closely packed cells embedded in a fibrillar or homogeneoussubstance. Sarcomas that may be treated with a compound, pharmaceuticalcomposition, or method provided herein include a chondrosarcoma,fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma,Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft partsarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma,chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrialsarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblasticsarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma,idiopathic multiple pigmented hemorrhagic sarcoma, immunoblastic sarcomaof B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen'ssarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma,leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma,reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovialsarcoma, or telangiectaltic sarcoma.

The term “melanoma” is taken to mean a tumor arising from themelanocytic system of the skin and other organs. Melanomas that may betreated with a compound, pharmaceutical composition, or method providedherein include, for example, acral-lentiginous melanoma, amelanoticmelanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma,Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma,malignant melanoma, nodular melanoma, subungal melanoma, or superficialspreading melanoma.

The term “carcinoma” refers to a malignant new growth made up ofepithelial cells tending to infiltrate the surrounding tissues and giverise to metastases. Exemplary carcinomas that may be treated with acompound, pharmaceutical composition, or method provided herein include,for example, medullary thyroid carcinoma, familial medullary thyroidcarcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma,adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenalcortex, alveolar carcinoma, alveolar cell carcinoma, basal cellcarcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamouscell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma,bronchogenic carcinoma, cerebriform carcinoma, cholangiocellularcarcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma,corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinomacutaneum, cylindrical carcinoma, cylindrical cell carcinoma, ductcarcinoma, ductal carcinoma, carcinoma durum, embryonal carcinoma,encephaloid carcinoma, epiermoid carcinoma, carcinoma epithelialeadenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum,gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma,carcinoma gigantocellulare, glandular carcinoma, granulosa cellcarcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellularcarcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroidcarcinoma, infantile embryonal carcinoma, carcinoma in situ,intraepidermal carcinoma, intraepithelial carcinoma, Krompecher'scarcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticularcarcinoma, carcinoma lenticulare, lipomatous carcinoma, lobularcarcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullarycarcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma,carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma,carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes,nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans,osteoid carcinoma, papillary carcinoma, periportal carcinoma,preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma,renal cell carcinoma of kidney, reserve cell carcinoma, carcinomasarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinomascroti, signet-ring cell carcinoma, carcinoma simplex, small-cellcarcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cellcarcinoma, carcinoma spongiosum, squamous carcinoma, squamous cellcarcinoma, string carcinoma, carcinoma telangiectaticum, carcinomatelangiectodes, transitional cell carcinoma, carcinoma tuberosum,tubular carcinoma, tuberous carcinoma, verrucous carcinoma, or carcinomavillosum.

Further examples of diseases, disorders, or conditions include, but arenot limited to viral diseases (e.g. herpesvirus infection associateddisease or hepatitis virus infection associated disease or HIV infectionassociated disease) associated with STAT3-dependent immunosuppression. Aviral disease associated with STAT3-dependent immunosuppression is adisease wherein the causative agent is a virus and wherein a symptom ofthe viral disease (i.e. virus infection) is immunosuppression dependenton STAT3. A herpesvirus infection associated disease is a diseasewherein the causative agent is a herpesvirus (e.g. HHV-1, HHV-4 HHV-5HHV-6A, HHV-6B, HHV-7, or HHV-8). A hepatitis infection associateddisease is a disease wherein the causative agent is a hepatitis virus(e.g. hepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitisD virus, or hepatitis E virus). An HIV infection associated disease is adisease wherein the causative agent is HIV. In embodiments, the viraldisease associated with STAT3-dependent immunosuppression is HSV-1infection and the causative agent is HHV-1 (herpes simplex virus-1,HSV-1). In embodiments, the viral disease associated withSTAT3-dependent immunosuppression is HSV-2 infection and the causativeagent is HHV-2 (herpes simplex virus-2, HSV-2). In embodiments, theviral disease associated with STAT3-dependent immunosuppression ischickenpox, shingles, or VZV infection, and the causative agent is HHV-3(varicella zoster virus, VZV). In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is infectiousmononucleosis, Burkitt's lymphoma, CNS lymphoma, post-transplantlymphoproliferative syndrome (PTLD), nasopharyngeal carcinoma, hairyleukoplakia, or CMV infection, and the causative agent is HHV-5(cytomegalovirus, CMV). In embodiments, the viral disease associatedwith STAT3-dependent immunosuppression is sixth disease, roseolainfantum, exanthema subitum, or HHV-6 infection and the causative agentis HHV-6A or HHV-6B (roseolovirus, herpes lymphotropic virus). Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is roseola infantum, exanthema subitum, or HHV-7infection and the causative agent is HHV-7 (pityriasis rosea). Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is Kaposi's sarcoma, primary effusion lymphoma,multicentric Castleman's disease, or HHV-8 infection and the causativeagent is HHV-8 (Kaposi's sarcoma-associated herpesvirus, KSHV). Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis A and the causative agent is hepatitis Avirus. In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis B and the causative agent is hepatitis Bvirus. In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis C and the causative agent is hepatitis Cvirus. In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis D and the causative agent is hepatitis Dvirus. In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis E and the causative agent is hepatitis Evirus. In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is HIV infection or AIDS and the causative agent isHIV (human immunodeficiency virus) (e.g. HIV-1 or HIV-2).

The term “signaling pathway” as used herein refers to a series ofinteractions between cellular and optionally extra-cellular components(e.g. proteins, nucleic acids, small molecules, ions, lipids) thatconveys a change in one component to one or more other components, whichin turn may convey a change to additional components, which isoptionally propagated to other signaling pathway components.

“Pharmaceutically acceptable excipient” and “pharmaceutically acceptablecarrier” refer to a substance that aids the administration of an activeagent to and absorption by a subject and can be included in thecompositions of the present invention without causing a significantadverse toxicological effect on the patient. Non-limiting examples ofpharmaceutically acceptable excipients include water, NaCl, normalsaline solutions, lactated Ringer's, normal sucrose, normal glucose,binders, fillers, disintegrants, lubricants, coatings, sweeteners,flavors, salt solutions (such as Ringer's solution), alcohols, oils,gelatins, carbohydrates such as lactose, amylose or starch, fatty acidesters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, andthe like. Such preparations can be sterilized and, if desired, mixedwith auxiliary agents such as lubricants, preservatives, stabilizers,wetting agents, emulsifiers, salts for influencing osmotic pressure,buffers, coloring, and/or aromatic substances and the like that do notdeleteriously react with the compounds of the invention. One of skill inthe art will recognize that other pharmaceutical excipients are usefulin the present invention.

The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

As used herein, the term “administering” means oral administration,administration as a suppository, topical contact, intravenous,parenteral, intraperitoneal, intramuscular, intralesional, intrathecal,intracranial, intranasal or subcutaneous administration, or theimplantation of a slow-release device, e.g., a mini-osmotic pump, to asubject. Administration is by any route, including parenteral andtransmucosal (e.g., buccal, sublingual, palatal, gingival, nasal,vaginal, rectal, or transdermal). In embodiments, administrationincludes direct administration to a tumor. Parenteral administrationincludes, e.g., intravenous, intramuscular, intra-arteriole,intradermal, subcutaneous, intraperitoneal, intraventricular, andintracranial. Other modes of delivery include, but are not limited to,the use of liposomal formulations, intravenous infusion, transdermalpatches, etc. By “co-administer” it is meant that a compositiondescribed herein is administered at the same time, just prior to, orjust after the administration of one or more additional therapies (e.g.anti-cancer agent or chemotherapeutic). The compound of the inventioncan be administered alone or can be coadministered to the patient.Coadministration is meant to include simultaneous or sequentialadministration of the compound individually or in combination (more thanone compound or agent). Thus, the preparations can also be combined,when desired, with other active substances (e.g. to reduce metabolicdegradation). The compositions of the present invention can be deliveredby transdermally, by a topical route, formulated as applicator sticks,solutions, suspensions, emulsions, gels, creams, ointments, pastes,jellies, paints, powders, and aerosols. Oral preparations includetablets, pills, powder, dragees, capsules, liquids, lozenges, cachets,gels, syrups, slurries, suspensions, etc., suitable for ingestion by thepatient. Solid form preparations include powders, tablets, pills,capsules, cachets, suppositories, and dispersible granules. Liquid formpreparations include solutions, suspensions, and emulsions, for example,water or water/propylene glycol solutions. The compositions of thepresent invention may additionally include components to providesustained release and/or comfort. Such components include high molecularweight, anionic mucomimetic polymers, gelling polysaccharides andfinely-divided drug carrier substrates. These components are discussedin greater detail in U.S. Pat. Nos. 4,911,920; 5,403,841; 5,212,162; and4,861,760. The entire contents of these patents are incorporated hereinby reference in their entirety for all purposes. The compositions of thepresent invention can also be delivered as microspheres for slow releasein the body. For example, microspheres can be administered viaintradermal injection of drug-containing microspheres, which slowlyrelease subcutaneously (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645,1995; as biodegradable and injectable gel formulations (see, e.g., GaoPharm. Res. 12:857-863, 1995); or, as microspheres for oraladministration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674,1997). In another embodiment, the formulations of the compositions ofthe present invention can be delivered by the use of liposomes whichfuse with the cellular membrane or are endocytosed, i.e., by employingreceptor ligands attached to the liposome, that bind to surface membraneprotein receptors of the cell resulting in endocytosis. By usingliposomes, particularly where the liposome surface carries receptorligands specific for target cells, or are otherwise preferentiallydirected to a specific organ, one can focus the delivery of thecompositions of the present invention into the target cells in vivo.(See, e.g., Al-Muhammed, J. Microencapsul. 13:293-306, 1996; Chonn,Curr. Opin. Biotechnol. 6:698-708, 1995; Ostro, Am. J. Hosp. Pharm.46:1576-1587, 1989). The compositions of the present invention can alsobe delivered as nanoparticles.

Pharmaceutical compositions provided by the present invention includecompositions wherein the active ingredient (e.g. compounds describedherein, including embodiments or examples) is contained in atherapeutically effective amount, i.e., in an amount effective toachieve its intended purpose. The actual amount effective for aparticular application will depend, inter alia, on the condition beingtreated. When administered in methods to treat a disease, suchcompositions will contain an amount of active ingredient effective toachieve the desired result, e.g., modulating the activity of a targetmolecule (e.g. a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6)), and/or reducing, eliminating, orslowing the progression of disease symptoms (e.g. symptoms of cancer(e.g. prostate cancer, castration-resistant prostate cancer, breastcancer, triple negative breast cancer, glioblastoma, ovarian cancer,lung cancer, squamous cell carcinoma (e.g head, neck, or esophagus),colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B celllymphoma, or multiple myeloma) or viral disease (e.g. herpesvirusinfection associated disease or hepatitis virus infection associateddisease or HIV infection associated disease)). Determination of atherapeutically effective amount of a compound of the invention is wellwithin the capabilities of those skilled in the art, especially in lightof the detailed disclosure herein.

The dosage and frequency (single or multiple doses) administered to amammal can vary depending upon a variety of factors, for example,whether the mammal suffers from another disease, and its route ofadministration; size, age, sex, health, body weight, body mass index,and diet of the recipient; nature and extent of symptoms of the diseasebeing treated (e.g. symptoms of cancer (e.g. prostate cancer,castration-resistant prostate cancer, breast cancer, triple negativebreast cancer, glioblastoma, ovarian cancer, lung cancer, squamous cellcarcinoma (e.g head, neck, or esophagus), colorectal cancer, leukemia,acute myeloid leukemia, lymphoma, B cell lymphoma, or multiplemyeloma)), kind of concurrent treatment, complications from the diseasebeing treated or other health-related problems. Other therapeuticregimens or agents can be used in conjunction with the methods andcompounds of Applicants' invention. Adjustment and manipulation ofestablished dosages (e.g., frequency and duration) are well within theability of those skilled in the art.

For any compound described herein, the therapeutically effective amountcan be initially determined from cell culture assays. Targetconcentrations will be those concentrations of active compound(s) thatare capable of achieving the methods described herein, as measured usingthe methods described herein or known in the art.

As is well known in the art, therapeutically effective amounts for usein humans can also be determined from animal models. For example, a dosefor humans can be formulated to achieve a concentration that has beenfound to be effective in animals. The dosage in humans can be adjustedby monitoring compounds effectiveness and adjusting the dosage upwardsor downwards, as described above. Adjusting the dose to achieve maximalefficacy in humans based on the methods described above and othermethods is well within the capabilities of the ordinarily skilledartisan.

Dosages may be varied depending upon the requirements of the patient andthe compound being employed. The dose administered to a patient, in thecontext of the present invention should be sufficient to effect abeneficial therapeutic response in the patient over time. The size ofthe dose also will be determined by the existence, nature, and extent ofany adverse side-effects. Determination of the proper dosage for aparticular situation is within the skill of the practitioner. Generally,treatment is initiated with smaller dosages which are less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under circumstances isreached.

Dosage amounts and intervals can be adjusted individually to providelevels of the administered compound effective for the particularclinical indication being treated. This will provide a therapeuticregimen that is commensurate with the severity of the individual'sdisease state.

Utilizing the teachings provided herein, an effective prophylactic ortherapeutic treatment regimen can be planned that does not causesubstantial toxicity and yet is effective to treat the clinical symptomsdemonstrated by the particular patient. This planning should involve thecareful choice of active compound by considering factors such ascompound potency, relative bioavailability, patient body weight,presence and severity of adverse side effects, preferred mode ofadministration and the toxicity profile of the selected agent.

The compounds described herein can be used in combination with oneanother, with other active agents known to be useful in treating cancer(e.g. prostate cancer, castration-resistant prostate cancer, breastcancer, triple negative breast cancer, glioblastoma, ovarian cancer,lung cancer, squamous cell carcinoma (e.g head, neck, or esophagus),colorectal cancer, leukemia, acute myeloid leukemia, lymphoma, B celllymphoma, or multiple myeloma), or with other active agents known to beuseful in treating viral disease (e.g. herpesvirus infection associateddisease or hepatitis virus infection associated disease or HIV infectionassociated disease), or with adjunctive agents that may not be effectivealone, but may contribute to the efficacy of the active agent.

In some embodiments, co-administration includes administering one activeagent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a secondactive agent. Co-administration includes administering two active agentssimultaneously, approximately simultaneously (e.g., within about 1, 5,10, 15, 20, or 30 minutes of each other), or sequentially in any order.In some embodiments, co-administration can be accomplished byco-formulation, i.e., preparing a single pharmaceutical compositionincluding both active agents. In other embodiments, the active agentscan be formulated separately. In another embodiment, the active and/oradjunctive agents may be linked or conjugated to one another. In someembodiments, the compounds described herein may be combined withtreatments for cancer (e.g. prostate cancer, castration-resistantprostate cancer, breast cancer, triple negative breast cancer,glioblastoma, ovarian cancer, lung cancer, squamous cell carcinoma (e.ghead, neck, or esophagus), colorectal cancer, leukemia, acute myeloidleukemia, lymphoma, B cell lymphoma, or multiple myeloma) such assurgery or with other treatments known to be useful in treating viraldisease (e.g. herpesvirus infection associated disease or hepatitisvirus infection associated disease or HIV infection associated disease).

The term “STAT” or “STAT transcription factor” are used interchangeablyand refer to a “Signal transducer and activator of transcription”protein and homologs thereof (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). In embodiments, “STAT transcription factor” refers toa human protein (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6). Included in the term “STAT transcription factor” are thewildtype and mutant forms of the protein (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6). In embodiments, “STAT transcriptionfactor” refers to the wildtype protein (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6). In embodiments, “STAT transcription factor”refers to a mutant protein (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). “Phosphorylated STAT” refers to a STAT protein (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) that isphosphorylated and activated by the phosphorylation. In embodiments,activation of a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) means the STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) is capable of activatingtranscription. In embodiments, activated STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) is phosphorylated on STAT1 Y701, STAT2,Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or aresidue corresponding to one of those residues, forms dimers (e.g.homodimers or heterodimers), translocates to the nucleus, and activatestranscription. In embodiments, activated STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) forms homodimers. In embodiments,activated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6) forms heterodimers. An example of a protein that phosphorylatesSTAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) andthereby activate a STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) includes JAK.

The term “STAT-binding nucleic acid sequence” refers to a nucleic acidcapable of binding to a STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) or a nucleic acid that forms part of a STAT-bindingsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding substituent). A STAT3-binding nucleic acid sequence is anucleic acid capable of binding to STAT3 or a nucleic acid that formspart of a STAT3-binding substituent (STAT3-binding nucleic acidsubstituent).

The term “STAT1” refers to a “Signal transducer and activator oftranscription 1” protein and homologs thereof. In embodiments, “STAT1”refers to the protein associated with Entrez Gene 6772, OMIM 600555,UniProt P42224, and/or RefSeq (protein) NP 009330. In embodiments, thereference numbers immediately above refer to the protein, and associatednucleic acids, known as of the date of filing of this application.

The term “STAT2” refers to a “Signal transducer and activator oftranscription 2” protein and homologs thereof. In embodiments, “STAT2”refers to the protein associated with Entrez Gene 6773, OMIM 600556,UniProt P52630, and/or RefSeq (protein) NP 005410. In embodiments, thereference numbers immediately above refer to the protein, and associatednucleic acids, known as of the date of filing of this application.

The term “STAT4” refers to a “Signal transducer and activator oftranscription 4” protein and homologs thereof. In embodiments, “STAT4”refers to the protein associated with Entrez Gene 6775, OMIM 600558,UniProt Q14765, and/or RefSeq (protein) NP 001230764. In embodiments,the reference numbers immediately above refer to the protein, andassociated nucleic acids, known as of the date of filing of thisapplication.

The term “STAT5A” refers to a “Signal transducer and activator oftranscription 5A” protein and homologs thereof. In embodiments, “STAT5A”refers to the protein associated with Entrez Gene 6776, OMIM 601511,UniProt P42229, and/or RefSeq (protein) NP 003143. In embodiments, thereference numbers immediately above refer to the protein, and associatednucleic acids, known as of the date of filing of this application.

The term “STAT5B” refers to a “Signal transducer and activator oftranscription 5B” protein and homologs thereof. In embodiments, “STAT5B”refers to the protein associated with Entrez Gene 6777, OMIM 604260,UniProt P51692, and/or RefSeq (protein) NP 036580. In embodiments, thereference numbers immediately above refer to the protein, and associatednucleic acids, known as of the date of filing of this application.

The term “STAT6” refers to a “Signal transducer and activator oftranscription 6” protein and homologs thereof. In embodiments, “STAT6”refers to the protein associated with Entrez Gene 6778, OMIM 601512,UniProt P42226, and/or RefSeq (protein) NP 001171549. In embodiments,the reference numbers immediately above refer to the protein, andassociated nucleic acids, known as of the date of filing of thisapplication.

The term “STAT3” refers to the protein “Signal transducer and activatorof transcription 3” and homologs thereof. In embodiments, “STAT3” refersto the human protein. Included in the term “STAT3” are the wildtype andmutant forms of the protein. In embodiments, “STAT3” refers to thewildtype protein. In embodiments, “STAT3” refers to a mutant protein. Inembodiments, “STAT3” refers to the protein associated with Entrez Gene6774, OMIM 102582, UniProt P40763, and/or RefSeq (protein) NP 003141. Inembodiments, the reference numbers immediately above refer to theprotein, and associated nucleic acids, known as of the date of filing ofthis application. “Phosphorylated STAT3” refers to a STAT3 protein thatis phosphorylated and activated by the phosphorylation. In embodiments,a phosphorylated STAT3 is phosphorylated on tyrosine 705 or the residuecorresponding to tyrosine 705 in homologs. In embodiments, activation ofSTAT3 means the STAT3 is capable of activating transcription. Inembodiments, activated STAT3 is phosphorylated on tyrosine 705, or theresidue corresponding to tyrosine 705, forms dimers (e.g. homodimers orheterodimers), translocates to the nucleus, and/or activatestranscription. In embodiments, activated STAT3 forms homodimers.Examples of proteins that phosphorylate STAT3 and thereby activate STAT3include JAK2, EGFR, c-MET, and PDGF-R.

“Anti-viral agent” is used in accordance with its plain ordinary meaningand refers to a composition (e.g. compound, drug, antagonist, inhibitor,modulator) having anti-infective properties or the ability to inhibitthe growth or proliferation of virus. In some embodiments, an anti-viralagent is an agent identified herein having utility in methods oftreating viral disease (e.g. herpesvirus infection associated disease orhepatitis virus infection associated disease or HIV infection associateddisease). In some embodiments, an anti-viral agent is an agent approvedby the FDA or similar regulatory agency of a country other than the USA,for treating viral disease (e.g. herpesvirus infection associateddisease or hepatitis virus infection associated disease or HIV infectionassociated disease). Examples of anti-viral agents are well known in theart and include agents for treating herpesvirus infection associateddisease, hepatitis virus infection associated disease, and HIV infectionassociated disease.

“Anti-cancer agent” is used in accordance with its plain ordinarymeaning and refers to a composition (e.g. compound, drug, antagonist,inhibitor, modulator) having antineoplastic properties or the ability toinhibit the growth or proliferation of cells. In some embodiments, ananti-cancer agent is a chemotherapeutic. In some embodiments, ananti-cancer agent is an agent identified herein having utility inmethods of treating cancer. In some embodiments, an anti-cancer agent isan agent approved by the FDA or similar regulatory agency of a countryother than the USA, for treating cancer. Examples of anti-cancer agentsinclude, but are not limited to, MEK (e.g. MEK1, MEK2, or MEK1 and MEK2)inhibitors (e.g. XL518, CI-1040, PD035901, selumetinib/AZD6244,GSK1120212/trametinib, GDC-0973, ARRY-162, ARRY-300, AZD8330, PD0325901,U0126, PD98059, TAK-733, PD318088, AS703026, BAY 869766), alkylatingagents (e.g., cyclophosphamide, ifosfamide, chlorambucil, busulfan,melphalan, mechlorethamine, uramustine, thiotepa, nitrosoureas, nitrogenmustards (e.g., mechloroethamine, cyclophosphamide, chlorambucil,meiphalan), ethylenimine and methylmelamines (e.g., hexamethlymelamine,thiotepa), alkyl sulfonates (e.g., busulfan), nitrosoureas (e.g.,carmustine, lomusitne, semustine, streptozocin), triazenes(decarbazine)), anti-metabolites (e.g., 5-azathioprine, leucovorin,capecitabine, fludarabine, gemcitabine, pemetrexed, raltitrexed, folicacid analog (e.g., methotrexate), or pyrimidine analogs (e.g.,fluorouracil, floxouridine, Cytarabine), purine analogs (e.g.,mercaptopurine, thioguanine, pentostatin), etc.), plant alkaloids (e.g.,vincristine, vinblastine, vinorelbine, vindesine, podophyllotoxin,paclitaxel, docetaxel, etc.), topoisomerase inhibitors (e.g.,irinotecan, topotecan, amsacrine, etoposide (VP16), etoposide phosphate,teniposide, etc.), antitumor antibiotics (e.g., doxorubicin, adriamycin,daunorubicin, epirubicin, actinomycin, bleomycin, mitomycin,mitoxantrone, plicamycin, etc.), platinum-based compounds (e.g.cisplatin, oxaloplatin, carboplatin), anthracenedione (e.g.,mitoxantrone), substituted urea (e.g., hydroxyurea), methyl hydrazinederivative (e.g., procarbazine), adrenocortical suppressant (e.g.,mitotane, aminoglutethimide), epipodophyllotoxins (e.g., etoposide),antibiotics (e.g., daunorubicin, doxorubicin, bleomycin), enzymes (e.g.,L-asparaginase), inhibitors of mitogen-activated protein kinasesignaling (e.g. U0126, PD98059, PD184352, PD0325901, ARRY-142886,SB239063, SP600125, BAY 43-9006, wortmannin, or LY294002), mTORinhibitors, antibodies (e.g., rituxan), 5-aza-2′-deoxycytidine,doxorubicin, vincristine, etoposide, gemcitabine, imatinib (Gleevec®),geldanamycin, 17-N-Allylamino-17-Demethoxygeldanamycin (17-AAG),bortezomib, trastuzumab, anastrozole; angiogenesis inhibitors;antiandrogen, antiestrogen; antisense oligonucleotides; apoptosis genemodulators; apoptosis regulators; arginine deaminase; BCR/ABLantagonists; beta lactam derivatives; bFGF inhibitor; bicalutamide;camptothecin derivatives; casein kinase inhibitors (ICOS); clomifeneanalogues; cytarabine dacliximab; dexamethasone; estrogen agonists;estrogen antagonists; etanidazole; etoposide phosphate; exemestane;fadrozole; finasteride; fludarabine; fluorodaunorunicin hydrochloride;gadolinium texaphyrin; gallium nitrate; gelatinase inhibitors;gemcitabine; glutathione inhibitors; hepsulfam; immunostimulantpeptides; insulin-like growth factor-1 receptor inhibitor; interferonagonists; interferons; interleukins; letrozole; leukemia inhibitingfactor; leukocyte alpha interferon; leuprolide+estrogen+progesterone;leuprorelin; matrilysin inhibitors; matrix metalloproteinase inhibitors;MIF inhibitor; mifepristone; mismatched double stranded RNA; monoclonalantibody; mycobacterial cell wall extract; nitric oxide modulators;oxaliplatin; panomifene; pentrozole; phosphatase inhibitors; plasminogenactivator inhibitor; platinum complex; platinum compounds; prednisone;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, protein tyrosine phosphataseinhibitors; purine nucleoside phosphorylase inhibitors; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;ribozymes; signal transduction inhibitors; signal transductionmodulators; single chain antigen-binding protein; stem cell inhibitor;stem-cell division inhibitors; stromelysin inhibitors; syntheticglycosaminoglycans; tamoxifen methiodide; telomerase inhibitors; thyroidstimulating hormone; translation inhibitors; tyrosine kinase inhibitors;urokinase receptor antagonists; steroids (e.g., dexamethasone),finasteride, aromatase inhibitors, gonadotropin-releasing hormoneagonists (GnRH) such as goserelin or leuprolide, adrenocorticosteroids(e.g., prednisone), progestins (e.g., hydroxyprogesterone caproate,megestrol acetate, medroxyprogesterone acetate), estrogens (e.g., diethlystilbestrol, ethinyl estradiol), antiestrogen (e.g., tamoxifen),androgens (e.g., testosterone propionate, fluoxymesterone), antiandrogen(e.g., flutamide), immunostimulants (e.g., Bacillus Calmette-Guerin(BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonalantibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, andanti-VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33monoclonal antibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.), triptolide, homoharringtonine, dactinomycin, doxorubicin,epirubicin, topotecan, itraconazole, vindesine, cerivastatin,vincristine, deoxyadenosine, sertraline, pitavastatin, irinotecan,clofazimine, 5-nonyloxytryptamine, vemurafenib, dabrafenib, erlotinib,gefitinib, EGFR inhibitors, epidermal growth factor receptor(EGFR)-targeted therapy or therapeutic (e.g. gefitinib (Iressa™)erlotinib (Tarceva™), cetuximab (Erbitux™), lapatinib (Tykerb™),panitumumab (Vectibix™) vandetanib (Caprelsa™), afatinib/BIBW2992,CI-1033/canertinib, neratinib/HKI-272, CP-724714, TAK-285, AST-1306,ARRY334543, ARRY-380, AG-1478, dacomitinib/PF299804, OSI-420/desmethylerlotinib, AZD8931, AEE788, pelitinib/EKB-569, CUDC-101, WZ8040, WZ4002,WZ3146, AG-490, XL647, PD153035, BMS-599626), sorafenib, imatinib,sunitinib, dasatinib, or the like.

“Chemotherapeutic” or “chemotherapeutic agent” is used in accordancewith its plain ordinary meaning and refers to a chemical composition orcompound having antineoplastic properties or the ability to inhibit thegrowth or proliferation of cells.

Additionally, the compounds described herein can be co-administered withconventional immunotherapeutic agents including, but not limited to,immunostimulants (e.g., Bacillus Calmette-Guérin (BCG), levamisole,interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g.,anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti-VEGF monoclonalantibodies), immunotoxins (e.g., anti-CD33 monoclonalantibody-calicheamicin conjugate, anti-CD22 monoclonalantibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy(e.g., anti-CD20 monoclonal antibody conjugated to ¹¹¹In, ⁹⁰Y, or ¹³¹I,etc.).

In a further embodiment, the compounds described herein can beco-administered with conventional radiotherapeutic agents including, butnot limited to, radionuclides such as ⁴⁷Sc, ⁶⁴Cu, ⁶⁷Cu, ⁸⁹Sr, ⁸⁶Y, ⁸⁷Y,⁹⁰Y, ¹⁰⁵Rh, ¹¹¹Ag, ¹¹¹In, ^(117m)Sn, ¹⁴⁹Pm, ¹⁵³Sm, ¹⁶⁶Ho, ¹⁷⁷Lu, ¹⁸⁶Re,¹⁸⁸Re, ²¹¹At and ²¹²Bi, optionally conjugated to antibodies directedagainst tumor antigens.

“Nucleic acid” or “oligonucleotide” or “polynucleotide” or grammaticalequivalents used herein means at least two nucleotides covalently linkedtogether. The term “nucleic acid” includes single-, double-, ormultiple-stranded DNA, RNA and analogs (derivatives) thereof.Oligonucleotides are typically from about 5, 6, 7, 8, 9, 10, 12, 15, 25,30, 40, 50 or more nucleotides in length, up to about 100 nucleotides inlength. Nucleic acids and polynucleotides are a polymers of any length,including longer lengths, e.g., 200, 300, 500, 1000, 2000, 3000, 5000,7000, 10,000, etc. In certain embodiments. the nucleic acids hereincontain phosphodiester bonds. In other embodiments, nucleic acid analogsare included that may have alternate backbones (e.g. phosphodiesterderivatives), including, e.g., phosphoramidate, phosphorodiamidate,phosphorothioate (also know as phosphothioate), phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, orO-methylphosphoroamidite linkages (see Eckstein, Oligonucleotides andAnalogues: A Practical Approach, Oxford University Press); and peptidenucleic acid backbones and linkages. Other analog nucleic acids includethose with positive backbones; non-ionic backbones, modified sugars, andnon-ribose backbones (e.g. phosphorodiamidate morpholino oligos orlocked nucleic acids (LNA)), including those described in U.S. Pat. Nos.5,235,033 and 5,034,506, and Chapters 6 and 7, ASC Symposium Series 580,Carbohydrate Modifications in Antisense Research, Sanghui & Cook, eds.Nucleic acids containing one or more carbocyclic sugars are alsoincluded within one definition of nucleic acids. Modifications of theribose-phosphate backbone may be done for a variety of reasons, e.g., toincrease the stability and half-life of such molecules in physiologicalenvironments or as probes on a biochip. Mixtures of naturally occurringnucleic acids and analogs can be made; alternatively, mixtures ofdifferent nucleic acid analogs, and mixtures of naturally occurringnucleic acids and analogs may be made. In embodiments, theinternucleotide linkages in DNA are phosphodiester, phosphodiesterderivatives, or a combination of both.

A particular nucleic acid sequence also encompasses “splice variants.”Similarly, a particular protein encoded by a nucleic acid encompassesany protein encoded by a splice variant of that nucleic acid. “Splicevariants,” as the name suggests, are products of alternative splicing ofa gene. After transcription, an initial nucleic acid transcript may bespliced such that different (alternate) nucleic acid splice productsencode different polypeptides. Mechanisms for the production of splicevariants vary, but include alternate splicing of exons. Alternatepolypeptides derived from the same nucleic acid by read-throughtranscription are also encompassed by this definition. Any products of asplicing reaction, including recombinant forms of the splice products,are included in this definition. An example of potassium channel splicevariants is discussed in Leicher, et al., J. Biol. Chem.273(52):35095-35101 (1998).

Nucleic acid is “operably linked” when it is placed into a functionalrelationship with another nucleic acid sequence. For example, DNA for apresequence or secretory leader is operably linked to DNA for apolypeptide if it is expressed as a preprotein that participates in thesecretion of the polypeptide; a promoter or enhancer is operably linkedto a coding sequence if it affects the transcription of the sequence; ora ribosome binding site is operably linked to a coding sequence if it ispositioned so as to facilitate translation. Generally, “operably linked”means that the DNA sequences being linked are near each other, and, inthe case of a secretory leader, contiguous and in reading phase.However, enhancers do not have to be contiguous. Linking is accomplishedby ligation at convenient restriction sites. If such sites do not exist,the synthetic oligonucleotide adaptors or linkers are used in accordancewith conventional practice.

An amino acid residue in a protein “corresponds” to a given residue whenit occupies the same essential structural position within the protein asthe given residue. For example, a selected residue in a selected protein(e.g. homolog of human STAT, STAT1, STAT2, STAT4, STAT5A, STAT5B, orSTAT6) corresponds to STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693,STAT5A Y694, STAT5B Y694, or STAT6 Y641 when the selected residueoccupies the same essential spatial or other structural relationship asSTAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5BY694, or STAT6 Y641 in each respective STAT protein. In someembodiments, where a selected protein is aligned for maximum homologywith the a STAT protein, the position in the aligned selected proteinaligning with STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5AY694, STAT5B Y694, or STAT6 Y641 is said to correspond to STAT1 Y701,STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, or STAT6Y641 respectively. Instead of a primary sequence alignment, a threedimensional structural alignment can also be used, e.g., where thestructure of the selected protein is aligned for maximum correspondencewith the a human STAT protein and the overall structures compared. Inthis case, an amino acid that occupies the same essential position asSTAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5BY694, or STAT6 Y641 in the structural model is said to correspond toSTAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5BY694, or STAT6 Y641.

The terms “identical” or percent “identity,” in the context of two ormore nucleic acids or polypeptide sequences, refer to two or moresequences or subsequences that are the same or have a specifiedpercentage of amino acid residues or nucleotides that are the same(i.e., about 60% identity, preferably 61%, 62%, 63%, 64%, 65%, 66%, 67%,68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%,82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%,96%, 97%, 98%, 99% or higher identity over a specified region whencompared and aligned for maximum correspondence over a comparison windowor designated region) as measured using a BLAST or BLAST 2.0 sequencecomparison algorithms with default parameters described below, or bymanual alignment and visual inspection (see, e.g., NCBI web site or thelike). Such sequences are then said to be “substantially identical.”This definition also refers to, or may be applied to, the compliment ofa test sequence. The definition also includes sequences that havedeletions and/or additions, as well as those that have substitutions. Asdescribed below, the preferred algorithms can account for gaps and thelike. Preferably, identity exists over a region that is at least about10 amino acids or 20 nucleotides in length, or more preferably over aregion that is 10-50 amino acids or 20-50 nucleotides in length. As usedherein, percent (%) amino acid sequence identity is defined as thepercentage of amino acids in a candidate sequence that are identical tothe amino acids in a reference sequence, after aligning the sequencesand introducing gaps, if necessary, to achieve the maximum percentsequence identity. Alignment for purposes of determining percentsequence identity can be achieved in various ways that are within theskill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN, ALIGN-2 or Megalign (DNASTAR)software. Appropriate parameters for measuring alignment, including anyalgorithms needed to achieve maximal alignment over the full-length ofthe sequences being compared can be determined by known methods.

For sequence comparisons, typically one sequence acts as a referencesequence, to which test sequences are compared. When using a sequencecomparison algorithm, test and reference sequences are entered into acomputer, subsequence coordinates are designated, if necessary, andsequence algorithm program parameters are designated. Preferably,default program parameters can be used, or alternative parameters can bedesignated. The sequence comparison algorithm then calculates thepercent sequence identities for the test sequences relative to thereference sequence, based on the program parameters.

A “comparison window”, as used herein, includes reference to a segmentof any one of the number of contiguous positions selected from the groupconsisting of from 10 to 600, usually about 50 to about 200, moreusually about 100 to about 150 in which a sequence may be compared to areference sequence of the same number of contiguous positions after thetwo sequences are optimally aligned. Methods of alignment of sequencesfor comparison are well-known in the art. Optimal alignment of sequencesfor comparison can be conducted, e.g., by the local homology algorithmof Smith & Waterman, Adv. Appl. Math. 2:482 (1981), by the homologyalignment algorithm of Needleman & Wunsch, J. Mol. Biol. 48:443 (1970),by the search for similarity method of Pearson & Lipman, Proc. Nat'l.Acad. Sci. USA 85:2444 (1988), by computerized implementations of thesealgorithms (GAP, BESTFIT, FASTA, and TFASTA in the Wisconsin GeneticsSoftware Package, Genetics Computer Group, 575 Science Dr., Madison,Wis.), or by manual alignment and visual inspection (see, e.g., CurrentProtocols in Molecular Biology (Ausubel et al., eds. 1995 supplement)).

The phrase “selectively (or specifically) hybridizes to” refers to thebinding, duplexing, or hybridizing of a molecule only to a particularnucleotide sequence with a higher affinity, e.g., under more stringentconditions, than to other nucleotide sequences (e.g., total cellular orlibrary DNA or RNA).

The phrase “stringent hybridization conditions” refers to conditionsunder which a probe will hybridize to its target subsequence, typicallyin a complex mixture of nucleic acids, but to no other sequences.Stringent conditions are sequence-dependent and will be different indifferent circumstances. Longer sequences hybridize specifically athigher temperatures. An extensive guide to the hybridization of nucleicacids is found in Tijssen, Techniques in Biochemistry and MolecularBiology—Hybridization with Nucleic Probes, “Overview of principles ofhybridization and the strategy of nucleic acid assays” (1993).Generally, stringent conditions are selected to be about 5-10° C. lowerthan the thermal melting point (T_(m)) for the specific sequence at adefined ionic strength pH. The T_(m) is the temperature (under definedionic strength, pH, and nucleic concentration) at which 50% of theprobes complementary to the target hybridize to the target sequence atequilibrium (as the target sequences are present in excess, at T_(m),50% of the probes are occupied at equilibrium). Stringent conditions mayalso be achieved with the addition of destabilizing agents such asformamide. For selective or specific hybridization, a positive signal isat least two times background, preferably 10 times backgroundhybridization. Exemplary stringent hybridization conditions can be asfollowing: 50% formamide, 5×SSC, and 1% SDS, incubating at 42° C., or,5×SSC, 1% SDS, incubating at 65° C., with wash in 0.2×SSC, and 0.1% SDSat 65° C.

Nucleic acids that do not hybridize to each other under stringentconditions are still substantially identical if the polypeptides whichthey encode are substantially identical. This occurs, for example, whena copy of a nucleic acid is created using the maximum codon degeneracypermitted by the genetic code. In such cases, the nucleic acidstypically hybridize under moderately stringent hybridization conditions.Exemplary “moderately stringent hybridization conditions” include ahybridization in a buffer of 40% formamide, 1 M NaCl, 1% SDS at 37° C.,and a wash in 1×SSC at 45° C. A positive hybridization is at least twicebackground. Those of ordinary skill will readily recognize thatalternative hybridization and wash conditions can be utilized to provideconditions of similar stringency. Additional guidelines for determininghybridization parameters are provided in numerous reference, e.g., andCurrent Protocols in Molecular Biology, ed. Ausubel, et al.

A “label” or a “detectable moiety” is a composition detectable byspectroscopic, photochemical, biochemical, immunochemical, chemical,magnetic resonance imaging, or other physical means. For example, usefuldetectable moieties include ³²P, fluorescent dyes, electron-densereagents, enzymes (e.g., as commonly used in an ELISA), biotin,digoxigenin, paramagnetic molecules, paramagnetic nanoparticles,ultrasmall superparamagnetic iron oxide (“USPIO”) nanoparticles, USPIOnanoparticle aggregates, superparamagnetic iron oxide (“SPIO”)nanoparticles, SPIO nanoparticle aggregates, monochrystalline SPIO,monochrystalline SPIO aggregates, monochrystalline iron oxidenanoparticles, monochrystalline iron oxide, other nanoparticle contrastagents, liposomes or other delivery vehicles containing Gadoliniumchelate (“Gd-chelate”) molecules, Gadolinium, radioisotopes,radionuclides (e.g. carbon-11, nitrogen-13, oxygen-15, fluorine-18,rubidium-82), fluorodeoxyglucose (e.g. fluorine-18 labeled), any gammaray emitting radionuclides, positron-emitting radionuclide, radiolabeledglucose, radiolabeled water, radiolabeled ammonia, biocolloids,microbubbles (e.g. including microbubble shells including albumin,galactose, lipid, and/or polymers; microbubble gas core including air,heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexanelipid microsphere, perflutren, etc.), iodinated contrast agents (e.g.iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide,diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide,gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores,two-photon fluorophores, or haptens and proteins or other entities whichcan be made detectable, e.g., by incorporating a radiolabel into apeptide or antibody specifically reactive with a target peptide.Detectable moieties also include any of the above compositionsencapsulated in nanoparticles, particles, aggregates, coated withadditional compositions, derivatized for binding to a targeting agent(e.g. compound described herein). Any method known in the art forconjugating an oligonucleotide or protein to the label may be employed,e.g., using methods described in Hermanson, Bioconjugate Techniques1996, Academic Press, Inc., San Diego.

MRI can be used to non-invasively acquire tissue images with highresolution. Paramagnetic agents or USPIO nanoparticles or aggregatesthereof enhance signal attenuation on T₂-weighted magnetic resonanceimages, and conjugation of such nanoparticles to binding ligands permitsthe detection of specific molecules at the cellular level. For example,MRI with nanoparticle detection agents can detect small foci of cancer.See e.g., Y. W. Jun et al., 2005, J. Am. Chem. Soc. 127:5732-5733; Y. M.Huh et al., 2005, J. Am. Chem. Soc. 127:12387-12391. Contrast-enhancedMRI is well-suited for the dynamic non-invasive imaging ofmacromolecules or of molecular events, but it requires ligands thatspecifically bind to the molecule of interest. J. W. Bulte et al., 2004,NMR Biomed. 17:484-499. Fluorescent dyes and fluorophores (e.g.fluorescein, fluorescein isothiocyanate, and fluorescein derivatives)can be used to non-invasively acquire tissue images with highresolution, with for example spectrophotometry, two-photon fluorescence,two-photon laser microscopy, or fluorescence microscopy (e.g. of tissuebiopsies). MRI can be used to non-invasively acquire tissue images withhigh resolution, with for example paramagnetic molecules, paramagneticnanoparticles, ultrasmall superparamagnetic iron oxide (“USPIO”)nanoparticles, USPIO nanoparticle aggregates, superparamagnetic ironoxide (“SPIO”) nanoparticles, SPIO nanoparticle aggregates,monochrystalline iron oxide nanoparticles, monochrystalline iron oxide,other nanoparticle contrast agents. MRI can be used to non-invasivelyacquire tissue images with high resolution, with for example Gadolinium,including liposomes or other delivery vehicles containing Gadoliniumchelate (“Gd-chelate”) molecules. Positron emission tomography (PET),PET/computed tomography (CT), single photon emission computed tomography(SPECT), and SPECT/CT can be used to non-invasively acquire tissueimages with high resolution, with for example radionuclides (e.g.carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium-82),fluorodeoxyglucose (e.g. fluorine-18 labeled), any gamma ray emittingradionuclides, positron-emitting radionuclide, radiolabeled glucose,radiolabeled water, radiolabeled ammonia. Ultrasound (ultrasonography)and contrast enhanced ultrasound (contrast enhanced ultrasonography) canbe used to non-invasively acquire tissue images with high resolution,with for example biocolloids or microbubbles (e.g. including microbubbleshells including albumin, galactose, lipid, and/or polymers; microbubblegas core including air, heavy gas(es), perfluorcarbon, nitrogen,octafluoropropane, perflexane lipid microsphere, perflutren, etc.).X-ray imaging (radiography) or CT can be used to non-invasively acquiretissue images with high resolution, with for example iodinated contrastagents (e.g. iohexol, iodixanol, ioversol, iopamidol, ioxilan,iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thoriumdioxide, gold, gold nanoparticles, or gold nanoparticle aggregates.These detection methods and instruments and detectable moieties capableof being measured or detected by the corresponding method arenon-limiting examples.

As used herein, the term “ultrasmall superparamagnetic iron oxidenanoparticle” or “USPIO nanoparticle” refers to superparamagnetic ironoxide particles ranging from 1 to 50 nm in diameter, more typicallybetween 5 and 40 nm in diameter (excluding any coating applied aftersynthesis). USPIO nanoparticles are commonly made of maghemite (Fe₂O₃)or magnetite (Fe₃O₄) having crystal-containing regions of unpairedspins. Those magnetic domains are disordered in the absence of amagnetic field, but when a field is applied (i.e., while taking an MRI),the magnetic domains align to create a magnetic moment much greater thanthe sum of the individual unpaired electrons without resulting inresidual magnetization of the particles.

As used herein, the term “TLR-binding nucleic acid substituent” refersto a substituent or moiety capable of binding to a toll-like receptor(“TLR”) or activating a toll-like receptor, including at least onenucleic acid. In embodiments, a TLR-binding nucleic acid substituent iscapable of binding a TLR. In embodiments, a TLR-binding nucleic acidsubstituent is capable of activating a TLR. In embodiments, aTLR-binding nucleic acid substituent is capable of activating a TLRwithout directly binding the TLR. In embodiments, a TLR-binding nucleicacid substituent is capable of binding a TLR without activating the TLR.In embodiments, a TLR-binding nucleic acid substituent is a nucleicacid. In embodiments, the TLR-binding nucleic acid substituent includesat least one nucleic acid analog. In embodiments, the TLR-bindingnucleic acid substituent includes at least one nucleic acid analoghaving an alternate backbone (e.g. phosphodiester derivative (e.g.phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite), peptide nucleic acidbackbone(s), LNA, or linkages). In embodiments, a TLR-binding nucleicacid substituent includes or is DNA. In embodiments, a TLR-bindingnucleic acid substituent includes or is RNA. In embodiments, aTLR-binding nucleic acid substituent includes or is a nucleic acidhaving internucleotide linkages selected from phosphodiesters andphosphodiester derivatives (e.g. phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, O-methylphosphoroamidite, orcombinations thereof). In embodiments, a TLR-binding nucleic acidsubstituent consists of a nucleic acid having internucleotide linkagesselected from phosphodiesters and phosphorothioates. In embodiments, aTLR-binding nucleic acid substituent includes or is a nucleic acidhaving backbone linkages selected from phosphodiesters andphosphorodithioates. In embodiments, a TLR-binding nucleic acidsubstituent includes or is a nucleic acid having phosphodiester backbonelinkages. In embodiments, a TLR-binding nucleic acid substituentincludes or is a nucleic acid having phosphorothioate backbone linkages.In embodiments, a TLR-binding nucleic acid substituent includes or is anucleic acid having phosphorodithioate backbone linkages. Inembodiments, a TLR-binding nucleic acid substituent preferentially bindsTLR9 over other TLR. In embodiments, a TLR-binding nucleic acidsubstituent specifically binds TLR9. In embodiments, a TLR-bindingnucleic acid substituent preferentially binds TLR3 over other TLR. Inembodiments, a TLR-binding nucleic acid substituent specifically bindsTLR3. In embodiments, a TLR-binding nucleic acid substituentpreferentially binds TLR7 over other TLR. In embodiments, a TLR-bindingnucleic acid substituent specifically binds TLR7. In embodiments, aTLR-binding nucleic acid substituent preferentially binds TLR8 overother TLR. In embodiments, a TLR-binding nucleic acid substituentspecifically binds TLR8. In embodiments, a TLR-binding nucleic acidsubstituent specifically binds a cellular subcompartment (e.g. endosome)associated TLR (e.g. TLR3, TLR7, TLR8, or TLR9). In embodiments, aTLR-binding nucleic acid substituent includes or is a G-rich nucleicacid (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% G nucleotides; 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100% G nucleotides). In embodiments, aTLR-binding nucleic acid substituent includes single stranded RNA(including phosphodiester internucleotide linkages, phosphodiesterderivative internucleotide linkages, or a combination both). Inembodiments, a TLR-binding nucleic acid substituent includes doublestranded RNA (including phosphodiester internucleotide linkages,phosphodiester derivative internucleotide linkages, or a combinationboth) (e.g. poly (I:C). In embodiments, a TLR-binding nucleic acidsubstituent is a TLR3-binding nucleic acid substituent. In embodiments,a TLR-binding nucleic acid substituent is a TLR7-binding nucleic acidsubstituent. In embodiments, a TLR-binding nucleic acid substituent is aTLR8-binding nucleic acid substituent. In embodiments, a TLR-bindingnucleic acid substituent is a TLR9-binding nucleic acid substituent. Inembodiments, a TLR-binding nucleic acid substituent is a TLR-binding DNAsubstituent. In embodiments, a TLR-binding nucleic acid substituent is aTLR9-binding DNA substituent.

As used herein, the term “TLR-binding DNA substituent” refers to asubstituent or moiety capable of binding to a toll-like receptor(“TLR”), including at least one deoxyribonucleic acid. In embodiments, aTLR-binding DNA substituent is a nucleic acid. In embodiments, theTLR-binding DNA substituent includes at least one nucleic acid analog.In embodiments, the TLR-binding DNA substituent includes at least onenucleic acid analog having an alternate backbone (e.g. phosphodiesterderivative (e.g. phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite), peptide nucleic acidbackbone(s), LNA, or linkages). In embodiments, a TLR-binding DNAsubstituent includes DNA. In embodiments, all nucleotide sugars in aTLR-binding DNA substituent are deoxyribose (e.g., all nucleotides areDNA). In embodiments, a TLR-binding DNA substituent consists of DNA. Inembodiments, a TLR-binding DNA substituent includes or is DNA havinginternucleotide linkages selected from phosphodiesters andphosphodiester derivatives (e.g. phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, O-methylphosphoroamidite, orcombinations thereof). In embodiments, a TLR-binding DNA substituentconsists of DNA having internucleotide linkages selected fromphosphodiesters and phosphorothioates. In embodiments, a TLR-binding DNAsubstituent includes or is DNA having backbone linkages selected fromphosphodiesters and phosphorodithioates. In embodiments, a TLR-bindingDNA substituent includes or is DNA including phosphodiester backbonelinkages. In embodiments, a TLR-binding DNA substituent includes or isDNA including phosphorothioate backbone linkages. In embodiments, aTLR-binding DNA substituent includes or is DNA includingphosphorodithioate backbone linkages. In embodiments, a TLR-binding DNAsubstituent preferentially binds TLR9 over other TLR. In embodiments, aTLR-binding DNA substituent specifically binds TLR9. In embodiments, aTLR-binding DNA substituent specifically binds TLR3. In embodiments, aTLR-binding DNA substituent specifically binds TLR7. In embodiments, aTLR-binding DNA substituent specifically binds TLR8. In embodiments, aTLR-binding DNA substituent specifically binds a cellular subcompartment(e.g. endosome) associated TLR (e.g. TLR3, TLR7, TLR8, or TLR9). Inembodiments, a TLR-binding DNA substituent includes or is a G-richoligonucleotide (e.g. about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13,14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67,68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% Gnucleotides; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% G nucleotides). Inembodiments, a TLR-binding DNA substituent includes a CpG motif, whereinC and G are nucleotides and p is the phosphate connecting the C and G.In embodiments, the CpG motif is unmethylated. In embodiments, aTLR-binding DNA substituent is a Class A CpG oligodeoxynucleotide (ODN).In embodiments, a TLR-binding DNA substituent is a Class B CpGoligodeoxynucleotide (ODN). In embodiments, a TLR-binding DNAsubstituent is a Class C CpG oligodeoxynucleotide (ODN). In embodiments,a TLR-binding DNA substituent (e.g., TLR9-binding DNA substituent)consists of deoxyribonucleic acids with A, G, C, or T bases andphosphodiester linkages and/or phosphodiester derivative linkages (e.g.,phosphorothioate linkage(s)).

As used herein, the term “CpG motif” refers to a 5′ C nucleotideconnected to a 3′ G nucleotide through a phosphodiester internucleotidelinkage or a phosphodiester derivative internucleotide linkage. Inembodiments, a CpG motif includes a phosphodiester internucleotidelinkage. In embodiments, a CpG motif includes a phosphodiesterderivative internucleotide linkage.

As used herein, the term “Class A CpG ODN” or “A-class CpG ODN” or“D-type CpG ODN” or “Class A CpG DNA sequence” is used in accordancewith its common meaning in the biological and chemical sciences andrefers to a CpG motif including oligodeoxynucleotide including one ormore of poly-G sequence at the 5′, 3′, or both ends; an internalpalindrome sequence including CpG motif; or one or more phosphodiesterderivatives linking deoxynucleotides. In embodiments, a Class A CpG ODNincludes poly-G sequence at the 5′, 3′, or both ends; an internalpalindrome sequence including CpG motif; and one or more phosphodiesterderivatives linking deoxynucleotides. In embodiments, the phosphodiesterderivative is phosphorothioate. Examples of Class A CpG ODNs include ODND19, ODN 1585, ODN 2216, and ODN 2336.

As used herein, the term “Class B CpG ODN” or “B-class CpG ODN” or“K-type CpG ODN” or “Class B CpG DNA sequence” is used in accordancewith its common meaning in the biological and chemical sciences andrefers to a CpG motif including oligodeoxynucleotide including one ormore of a 6mer motif including a CpG motif; phosphodiester derivativeslinking all deoxynucleotides. In embodiments, a Class B CpG ODN includesone or more copies of a 6mer motif including a CpG motif andphosphodiester derivatives linking all deoxynucleotides. In embodiments,the phosphodiester derivative is phosphorothioate. In embodiments, aClass B CpG ODN includes one 6mer motif including a CpG motif. Inembodiments, a Class B CpG ODN includes two copies of a 6mer motifincluding a CpG motif. In embodiments, a Class B CpG ODN includes threecopies of a 6mer motif including a CpG motif. In embodiments, a Class BCpG ODN includes four copies of a 6mer motif including a CpG motif.Examples of Class B CpG ODNs include ODN 1668, ODN 1826, ODN 2006, andODN 2007.

As used herein, the term “Class C CpG ODN” or “C-class CpG ODN” or“C-type CpG DNA sequence” is used in accordance with its common meaningin the biological and chemical sciences and refers to anoligodeoxynucleotide including a palindrome sequence including a CpGmotif and phosphodiester derivatives (phosphorothioate) linking alldeoxynucleotides. Examples of Class C CpG ODNs include ODN 2395 and ODNM362.

As used herein, the term “STAT-binding substituent” or “STAT-bindingnucleic acid substituent” refers to a composition including one or morenucleic acids capable of binding to a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments, aSTAT-binding substituent includes DNA (e.g. including phosphodiesterinternucleotide linkages, phosphodiester derivative internucleotidelinkages, or a combination of phosphodiester and phosphodiesterderivative internucleotide linkages). In embodiments, a STAT-bindingsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding substituent) includes a DNA sequence identical (exceptthat it may include one or more phosphodiester derivative linkage(s)) tothe genomic DNA sequence a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) binds when modulatingtranscription. In embodiments, a STAT-binding substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding substituent)is a DNA sequence identical (except that it may include one or morephosphodiester derivative linkage(s)) to the genomic DNA sequence a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) binds when modulating transcription. In embodiments, aSTAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding substituent) includes a DNA sequence identical(except that it may include one or more phosphodiester derivativelinkage(s)) to the genomic DNA sequence phosphorylated (e.g. on STAT1Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694,STAT6 Y641, or a residue corresponding to one of those residues) STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) binds whenmodulating transcription. In embodiments, a STAT-binding substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingsubstituent) is a DNA sequence identical (except that it may include oneor more phosphodiester derivative linkage(s)) to the genomic DNAsequence phosphorylated (e.g. on STAT1 Y701, STAT2, Y690, STAT3 Y705,STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or a residuecorresponding to one of those residues) STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) binds when modulating transcription. Inembodiments, a STAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding substituent) includes a DNAsequence identical (except that it may include one or morephosphodiester derivative linkage(s)) to the genomic DNA sequence a STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinationsthereof) dimer binds when modulating transcription. In embodiments, aSTAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding substituent) is a DNA sequence identical(except that it may include one or more phosphodiester derivativelinkage(s)) to the genomic DNA sequence a STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) dimerbinds when modulating transcription. In embodiments, a STAT-bindingsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding substituent) includes a DNA sequence identical (exceptthat it may include one or more phosphodiester derivative linkage(s)) tothe genomic DNA sequence a phosphorylated (e.g. on STAT1 Y701, STAT2,Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or aresidue corresponding to one of those residues) STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) dimerbinds when modulating transcription. In embodiments, a STAT-bindingsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding substituent) is a DNA sequence identical (except that itmay include one or more phosphodiester derivative linkage(s)) to thegenomic DNA sequence a phosphorylated (e.g. on STAT1 Y701, STAT2, Y690,STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or aresidue corresponding to one of those residues) STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) dimerbinds when modulating transcription.

As used herein, the term “STAT3-binding nucleic acid substituent” or“STAT3-binding substituent” refers to a composition including one ormore nucleic acids capable of binding to STAT3. In embodiments, aSTAT3-binding substituent includes DNA (e.g. including phosphodiesterinternucleotide linkages, phosphodiester derivative internucleotidelinkages, or a combination of phosphodiester and phosphodiesterderivative internucleotide linkages) (a “STAT3-binding DNAsubstituent”). In embodiments, all nucleotide sugars in a STAT3-bindingDNA substituent are deoxyribose (e.g., all nucleotides are DNA). Inembodiments, a STAT3-binding substituent is DNA (e.g. includingphosphodiester internucleotide linkages, phosphodiester derivativeinternucleotide linkages, or a combination of phosphodiester andphosphodiester derivative internucleotide linkages). In embodiments, aSTAT3-binding substituent includes a DNA sequence identical (except thatit may include one or more phosphodiester derivative linkage(s)) to thegenomic DNA sequence STAT3 binds when modulating transcription. Inembodiments, a STAT3-binding substituent is a DNA sequence identical(except that it may include one or more phosphodiester derivativelinkage(s)) to the genomic DNA sequence STAT3 binds when modulatingtranscription. In embodiments, a STAT3-binding substituent includes aDNA sequence identical (except that it may include one or morephosphodiester derivative linkage(s)) to the genomic DNA sequencephosphorylated (e.g. on Y705 or residue corresponding to human STAT3Y705) STAT3 binds when modulating transcription. In embodiments, aSTAT3-binding substituent is a DNA sequence identical (except that itmay include one or more phosphodiester derivative linkage(s)) to thegenomic DNA sequence phosphorylated (e.g. on Y705 or residuecorresponding to human STAT3 Y705) STAT3 binds when modulatingtranscription. In embodiments, a STAT3-binding substituent includes aDNA sequence identical (except that it may include one or morephosphodiester derivative linkage(s)) to the genomic DNA sequence aSTAT3 dimer binds when modulating transcription. In embodiments, aSTAT3-binding substituent is a DNA sequence identical (except that itmay include one or more phosphodiester derivative linkage(s)) to thegenomic DNA sequence a STAT3 dimer binds when modulating transcription.In embodiments, a STAT3-binding substituent includes a DNA sequenceidentical (except that it may include one or more phosphodiesterderivative linkage(s)) to the genomic DNA sequence a phosphorylated(e.g. on Y705 or residue corresponding to human STAT3 Y705) STAT3 dimerbinds when modulating transcription. In embodiments, a STAT3-bindingsubstituent is a DNA sequence identical (except that it may include oneor more phosphodiester derivative linkage(s)) to the genomic DNAsequence a phosphorylated (e.g. on Y705 or residue corresponding tohuman STAT3 Y705) STAT3 dimer binds when modulating transcription. Inembodiments, a STAT3-binding substituent includes the DNA (e.g.including phosphodiester linkages and/or phosphodiester derivativelinkages) sequence CATTTCCCGTAAATC (SEQ ID NO:1). In embodiments, aSTAT3-binding substituent includes the complement to DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence CATTTCCCGTAAATC (SEQ ID NO:1). In embodiments, a STAT3-bindingsubstituent includes the DNA (e.g. including phosphodiester linkagesand/or phosphodiester derivative linkages) sequence CATTTCCCGTAAATC (SEQID NO:1) and the complement of the sequence. In embodiments, aSTAT3-binding substituent includes the DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence ATTTCCCGTAAAT (SEQ ID NO:2). In embodiments, a STAT3-bindingsubstituent includes the complement to DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence ATTTCCCGTAAAT (SEQ ID NO:2). In embodiments, a STAT3-bindingsubstituent includes the DNA (e.g. including phosphodiester linkagesand/or phosphodiester derivative linkages) sequence ATTTCCCGTAAAT (SEQID NO:2) and the complement of the sequence. In embodiments, aSTAT3-binding substituent includes the DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTTCCCGTAAA (SEQ ID NO:3). In embodiments, a STAT3-bindingsubstituent includes the complement to DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTTCCCGTAAA (SEQ ID NO:3). In embodiments, a STAT3-bindingsubstituent includes the DNA (e.g. including phosphodiester linkagesand/or phosphodiester derivative linkages) sequence TTTCCCGTAAA (SEQ IDNO:3) and the complement of the sequence. In embodiments, aSTAT3-binding substituent includes the DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTCCCGTAA (SEQ ID NO:4). In embodiments, a STAT3-bindingsubstituent includes the complement to DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTCCCGTAA (SEQ ID NO:4). In embodiments, a STAT3-bindingsubstituent includes the DNA (e.g. including phosphodiester linkagesand/or phosphodiester derivative linkages) sequence TTCCCGTAA (SEQ IDNO:4) and the complement of the sequence. In embodiments, aSTAT3-binding substituent includes the DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTCCGGGAA (SEQ ID NO:5). In embodiments, a STAT3-bindingsubstituent includes the complement to DNA (e.g. includingphosphodiester linkages and/or phosphodiester derivative linkages)sequence TTCCGGGAA (SEQ ID NO:5). In embodiments, a STAT3-bindingsubstituent includes the DNA (e.g. including phosphodiester linkagesand/or phosphodiester derivative linkages) sequence TTCCGGGAA (SEQ IDNO:5) and the complement of the sequence.

As used herein, the term “preferentially binds” as applied to aSTAT-binding substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding substituent) or STAT3-binding nucleic acidsubstituent (e.g. STAT3-binding DNA substituent) binding to a specificform of a STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) or STAT3 respectively, means binds morestrongly to the specific form compared to the binding to another form ofa STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). In embodiments, preferentially binds means binds morestrongly to the specific form compared to the binding to other forms ofa STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). In embodiments, preferential binding is measured asan IC50. In embodiments, preferential binding is measured as adissociation constant. In embodiments, preferential binding is measuredas an association constant. In embodiments, preferential binding ismeasured as an on rate. In embodiments, preferential binding is measuredas an off rate. In embodiments, preferential binding is measured as alowered concentration needed to bind to the preferred form to the sameextent as binding to a non-preferred form at a greater concentration. Inembodiments, preferentially binds means binds 1.1-fold, 1.2-fold,1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold,2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold,20-fold, 30-fold, 40-fold, 50-fold, 60-fold, 70-fold, 80-fold, 90-fold,100-fold, 200-fold, 300-fold, 400-fold, 500-fold, 600-fold, 700-fold,800-fold, 900-fold, 1000-fold, 2000-fold, 3000-fold, 4000-fold,5000-fold, 6000-fold, 7000-fold, 8000-fold, 9000-fold, 10000 fold,100,000-fold, or 1,000,000-fold greater to the preferred form comparedto another form. In embodiments, preferentially binds means binds1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold,1.8-fold, 1.9-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold,8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 40-fold, 50-fold, 60-fold,70-fold, 80-fold, 90-fold, 100-fold, 200-fold, 300-fold, 400-fold,500-fold, 600-fold, 700-fold, 800-fold, 900-fold, 1000-fold, 2000-fold,3000-fold, 4000-fold, 5000-fold, 6000-fold, 7000-fold, 8000-fold,9000-fold, 10000 fold, 100,000-fold, or 1,000,000-fold greater to thepreferred form compared to other forms.

As used herein, the term “conjugated” when referring to two moietiesmeans the two moieties are bonded, wherein the bond or bonds connectingthe two moieties may be covalent or non-covalent. In embodiments, thetwo moieties are covalently bonded to each other (e.g. directly orthrough a covalently bonded intermediary). In embodiments, the twomoieties are non-covalently bonded (e.g. through ionic bond(s), van derwaal's bond(s)/interactions, hydrogen bond(s), polar bond(s), orcombinations or mixtures thereof).

As used herein, the term “about” means a range of values including thespecified value, which a person of ordinary skill in the art wouldconsider reasonably similar to the specified value. In embodiments,about means within a standard deviation using measurements generallyacceptable in the art. In embodiments, about means a range extending to+/−10% of the specified value. In embodiments, about means the specifiedvalue.

Compounds

In an aspect is provided a compound including a TLR-binding (e.g.endosome-associated TLR-(endosomal TLR-), TLR3-, TLR7-, TLR8-, orTLR9-binding) nucleic acid substituent conjugated to a STAT-bindingsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding substituent). In embodiments the compound includes aTLR9-binding DNA substituent conjugated to a STAT-binding substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingsubstituent). In embodiments, the compound includes a TLR9-binding DNAsubstituent conjugated to a STAT3-binding substituent. In embodiments,the STAT-binding substituent is a STAT1-binding substituent. Inembodiments, the STAT-binding substituent is a STAT2-bindingsubstituent. In embodiments, the STAT-binding substituent is aSTAT3-binding substituent. In embodiments, the STAT-binding substituentis a STAT4-binding substituent. In embodiments, the STAT-bindingsubstituent is a STAT5A-binding substituent. In embodiments, theSTAT-binding substituent is a STAT5B-binding substituent. Inembodiments, the STAT-binding substituent is a STAT6-bindingsubstituent. In embodiments, the TLR-binding nucleic acid substituent isan endosome-associated TLR-binding nucleic acid substituent. Inembodiments, the TLR-binding nucleic acid substituent is a TLR3-bindingnucleic acid substituent. In embodiments, the TLR-binding nucleic acidsubstituent is a TLR7-binding nucleic acid substituent. In embodiments,the TLR-binding nucleic acid substituent is a TLR8-binding nucleic acidsubstituent. In embodiments, the TLR-binding nucleic acid substituent isa TLR9-binding nucleic acid substituent. In embodiments, the TLR-bindingnucleic acid substituent is a TLR9-binding DNA substituent. Inembodiments, the STAT-binding substituent is a STAT-binding nucleic acidsubstituent. In embodiments, the STAT-binding substituent is aSTAT3-binding nucleic acid substituent (e.g. STAT3-binding DNAsubstituent). In embodiments, the STAT-binding substituent is aSTAT3-binding DNA substituent.

In embodiments, the compound includes a CpG motif. In embodiments, thecompound includes an unmethylated CpG motif. In embodiments, thecompound includes a CpG motif wherein the CpG is not methylated. Inembodiments, the compound includes a nucleic acid sequence capable offorming a G-quadruplex. In embodiments, the compound includes a DNAsequence capable of forming a G-quadruplex. In embodiments, the compoundincludes a Class A CpG DNA sequence. In embodiments, the compoundincludes a Class B CpG DNA sequence. In embodiments, the compoundincludes a C-type CpG DNA sequence. In embodiments, the compound bindsan endosomal TLR. In embodiments, the compound preferentially binds anendosomal TLR over other TLR. In embodiments, the compound specificallybinds an endosomal TLR. In embodiments, the compound binds TLR3. Inembodiments, the compound preferentially binds TLR3 over other TLR. Inembodiments, the compound specifically binds TLR3. In embodiments, thecompound binds TLR7. In embodiments, the compound preferentially bindsTLR7 over other TLR. In embodiments, the compound specifically bindsTLR7. In embodiments, the compound binds TLR8. In embodiments, thecompound preferentially binds TLR8 over other TLR. In embodiments, thecompound specifically binds TLR8. In embodiments, the compound bindsTLR9. In embodiments, the compound preferentially binds TLR9 over otherTLR. In embodiments, the compound specifically binds TLR9. Inembodiments, the compound includes CpG, wherein C and G are nucleotidesconnected by a phosphodiester internucleotide linkage or phosphodiesterderivative internucleotide linkage. In embodiments, the compoundincludes CpG, wherein C and G are nucleotides connected by aphosphodiester internucleotide linkage. In embodiments, the compoundincludes CpG, wherein C and G are nucleotides connected by aphosphodiester derivative internucleotide linkage. In embodiments, theCpG is unmethylated. In embodiments, the compound preferentially bindsphosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6) over unphosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6). In embodiments, the compound bindsphosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6). In embodiments, the compound binds STAT3 phosphorylated ontyrosine 705. In embodiments, the compound binds a STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)phosphorylated on STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693,STAT5A Y694, STAT5B Y694, STAT6 Y641, or a residue corresponding to oneof those residues. In embodiments, the compound binds human STAT (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments,the compound binds STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, STAT6, or combinations thereof) dimers. In embodiments, thecompound binds dimers of phosphorylated STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) (e.g.phosphorylated on STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693,STAT5A Y694, STAT5B Y694, STAT6 Y641, or a residue corresponding to oneof those residues). In embodiments, the compound binds activated STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). Inembodiments, the compound binds a scavenger receptor.

In embodiments, the compound enters a cell following administration(e.g. to a patient, to the blood stream of a patient, or to theextracellular milieu of the cell) in about 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 118, 119, 120 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,114, 115, 116, 117, 118, 119, or 120 hours. In embodiments, the compoundenters a cell following administration (e.g. to a patient, to the bloodstream of a patient, or to the extracellular milieu of the cell) in lessthan 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107,108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120 minutes,1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56,57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74,75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, or 120 hours. Inembodiments, the compound enters a cell following administration (e.g.to a patient, to the blood stream of a patient, or to the extracellularmilieu of the cell) without co-administration of an agent to facilitatetransfection (e.g. an agent with the sole purpose of assisting thecompound to enter a cell). In embodiments, the cell is a plasmacytoiddendritic cell, myeloid dendritic cell, myeloid-derived suppressor cell,granulocytic myeloid-derived suppressor cell, macrophage, B cell,activated NK cell, or activated neutrophil. In embodiments, the cell isin the brain, an organ, bone, or bone marrow of a subject.

In embodiments, the compound is not degraded (e.g. in a patient, in theblood stream, at the site of administration, or in the extracellularmilieu) for about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104,105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,119, 120 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70,71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88,89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104,105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118,119, or 120 hours. In embodiments, the compound is not degraded (e.g. ina patient, in the blood stream, at the site of administration, or in theextracellular milieu) for an average of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, 120 minutes, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100,101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114,115, 116, 117, 118, 119, or 120 hours. In embodiments, the compound isnot degraded (e.g. in a patient, in the blood stream, at the site ofadministration, or in the extracellular milieu) for at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110,111, 112, 113, 114, 115, 116, 117, 118, 119, 120 minutes, 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,112, 113, 114, 115, 116, 117, 118, 119, or 120 hours.

In embodiments, the STAT3-binding nucleic acid substituent (e.g.STAT3-binding DNA substituent) includes a first STAT3-binding nucleicacid sequence (e.g. STAT3-binding DNA sequence) bound to a secondSTAT3-binding nucleic acid sequence (e.g. STAT3-binding DNA sequence) bya spacer. In embodiments, the STAT3-binding nucleic acid substituent(e.g. STAT3-binding DNA substituent) includes a first STAT3-bindingnucleic acid sequence (e.g. STAT3-binding DNA sequence) covalently boundto a second STAT3-binding nucleic acid sequence (e.g. STAT3-binding DNAsequence) by a spacer. In embodiments, the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent) includes a first STAT-bindingnucleic acid sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding nucleic acid sequence) bound to a secondSTAT-binding nucleic acid sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding nucleic acid sequence) by a spacer.In embodiments, the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent) includes a first STAT-binding nucleic acid sequence (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid sequence) covalently bound to a second STAT-binding nucleicacid sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid sequence) by a spacer.

In embodiments, the STAT3-binding DNA substituent includes a firstSTAT3-binding DNA sequence bound to a second STAT3-binding DNA sequenceby a spacer. In embodiments, the STAT3-binding DNA substituent includesa first STAT3-binding DNA sequence covalently bound to a secondSTAT3-binding DNA sequence by a spacer. In embodiments, the STAT-bindingDNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-,or STAT6-binding DNA substituent) includes a first STAT-binding DNAsequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence) bound to a second STAT-binding DNA sequence(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingDNA sequence) by a spacer. In embodiments, the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent) includes a first STAT-binding DNAsequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence) covalently bound to a second STAT-bindingDNA sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence) by a spacer.

In embodiments, the TLR9-binding DNA substituent includes a CpG motif.In embodiments, the TLR9-binding DNA substituent includes anunmethylated CpG motif. In embodiments, the TLR9-binding DNA substituentincludes a CpG motif wherein the CpG is not methylated. In embodiments,the TLR9-binding DNA substituent includes a DNA sequence capable offorming a G-quadruplex. In embodiments, the TLR9-binding DNA substituentincludes a Class A CpG DNA sequence. In embodiments, the TLR9-bindingDNA substituent includes a Class B CpG DNA sequence. In embodiments, theTLR9-binding DNA substituent includes a C-type CpG DNA sequence.

In embodiments, the TLR-binding DNA substituent binds TLR9. Inembodiments, the TLR-binding DNA substituent preferentially binds TLR9over other TLR. In embodiments, the TLR-binding DNA substituentspecifically binds TLR9. In embodiments, the TLR-binding DNA substituentincludes CpG, wherein C and G are nucleotides connected by aphosphodiester internucleotide linkage or phosphodiester derivativeinternucleotide linkage. In embodiments, the compound includes CpG,wherein C and G are nucleotides connected by a phosphodiesterinternucleotide linkage. In embodiments, the compound includes CpG,wherein C and G are nucleotides connected by a phosphodiester derivativeinternucleotide linkage. In embodiments, the CpG is unmethylated. Inembodiments, the TLR-binding DNA substituent is a Class A CpGoligodeoxynucleotide (ODN). In embodiments, the TLR-binding DNAsubstituent is a Class B CpG oligodeoxynucleotide (ODN). In embodiments,the TLR-binding DNA substituent is a Class C CpG oligodeoxynucleotide(ODN). In embodiments, the TLR-binding DNA substituent is ODN 1585, ODN2216, ODN D19, or ODN 2336. In embodiments, the TLR-binding DNAsubstituent is ODN 1668, ODN 1826, ODN 2006, or ODN 2007. Inembodiments, the TLR-binding DNA substituent is ODN 2395 or ODN M362. Inembodiments, the TLR-binding DNA substituent is a derivative of ODN1585, ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN2007, ODN 2395 or ODN M362. In embodiments, a derivative of ODN 1585,ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN2395 or ODN M362 includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,or 100) nucleotide substitutions (e.g. A, C, G, or T substituted with adifferent nucleotide). In embodiments, a derivative of ODN 1585, ODN2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN 2007, ODN2395 or ODN M362 includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,or 100) internucleotide linkage replacements (e.g. phosphodiesterreplaced with a phosphodiester derivative or a phosphodiester derivativereplaced with a phosphodiester). In embodiments, a derivative of ODN1585, ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN2007, ODN 2395 or ODN M362 includes one or more (e.g. 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100) nucleotide deletions. In embodiments, a derivative ofODN 1585, ODN 2216, ODN D19, ODN 2336, ODN 1668, ODN 1826, ODN 2006, ODN2007, ODN 2395 or ODN M362 includes one or more (e.g. 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or 100) nucleotide additions.

A spacer is a bond, nucleic acid sequence, two nucleic acid sequences,DNA sequence, two DNA sequences, nucleic acid analog sequence,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene.

In embodiments, the spacer is a substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, the spaceris a substituted or unsubstituted C₁-C₂₀ alkylene, substituted orunsubstituted 2 to 20 membered heteroalkylene, substituted orunsubstituted C₃-C₈ cycloalkylene, substituted or unsubstituted 3 to 8membered heterocycloalkylene, substituted or unsubstituted C₆-C₁₀arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.In embodiments, the spacer is an unsubstituted C₁-C₂₀ alkylene,unsubstituted 2 to 20 membered heteroalkylene, unsubstituted C₃-C₈cycloalkylene, unsubstituted 3 to 8 membered heterocycloalkylene,unsubstituted C₆-C₁₀ arylene, or unsubstituted 5 to 10 memberedheteroarylene. In embodiments, the spacer is an unsubstituted C₁-C₂₀alkylene. In embodiments, the spacer is a substituted or unsubstitutedC₁-C₄₀ alkylene, substituted or unsubstituted 2 to 40 memberedheteroalkylene, substituted or unsubstituted C₃-C₈ cycloalkylene,substituted or unsubstituted 3 to 8 membered heterocycloalkylene,substituted or unsubstituted C₆-C₁₀ arylene, or substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, the spaceris a substituted or unsubstituted C₁-C₄₀ alkylene. In embodiments, thespacer is a substituted or unsubstituted 2 to 40 memberedheteroalkylene. In embodiments, the spacer is a substituted 2 to 40membered heteroalkylene. In embodiments, the spacer includes alkylphosphates (e.g., propyl phosphates). In embodiments, the spacerconsists of alkyl phosphates (e.g., propyl phosphates) bonded to thereminder of the compound by phosphates at both ends. In embodiments, thespacer consists of 1-5 alkyl phosphates (e.g., propyl phosphates) bondedto the reminder of the compound by phosphates at both ends. Inembodiments, the spacer consists of 1-4 alkyl phosphates (e.g., propylphosphates) bonded to the reminder of the compound by phosphates at bothends. In embodiments, the spacer consists of 4 alkyl phosphates (e.g.,propyl phosphates) bonded to the reminder of the compound by phosphatesat both ends. A person having ordinary skill in the art will recognizethat a spacer consisting of alkyl phosphates that is bonded to theremainder of the compound by phosphates on both ends will have one morephosphate than alkylene groups (e.g., a spacer consisting of 4 alkylphosphates that is bonded to the reminder of the compound by phosphatesat both ends will have five phosphates and four alkyl groups withalternating phosphate groups and alkyl groups).

In embodiments, the spacer includes a first single nucleic acid strandconnected to the first STAT3-binding nucleic acid sequence (e.g.STAT3-binding DNA sequence) and a second single nucleic acid strandconnected to the second STAT3-binding nucleic acid sequence (e.g.STAT3-binding DNA sequence), wherein the first nucleic acid strandincludes a nucleic acid sequence that is complementary to a nucleic acidsequence included in the second single nucleic acid strand (both singlenucleic acid strands including their respective complementary sequencesbeing collectively a “hybridized nucleic acid overhang”. In embodiments,the spacer includes a first single nucleic acid strand connected to thefirst STAT-binding nucleic acid sequence (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acid sequence) and asecond single nucleic acid strand connected to the STAT-binding nucleicacid sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid sequence), wherein the first nucleic acidstrand includes a nucleic acid sequence that is complementary to anucleic acid sequence included in the second single nucleic acid strand(both single nucleic acid strands including their respectivecomplementary sequences being collectively a “hybridized nucleic acidoverhang”. In embodiments, the hybridized nucleic acid overhang is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100 base pairs long. In embodiments, thecomplementary nucleic acid sequence in the hybridized nucleic acidoverhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 base pairs long. Inembodiments, the first and second single nucleic acid strands in thehybridized nucleic acid overhang are complementary throughout theirentire lengths. In embodiments, the spacer is an unsubstituted C₁-C₂₀alkylene. In embodiments, the spacer is an unsubstituted linear C₁-C₂₀alkylene. In embodiments, the spacer is an unsubstituted C₃-C₂₁alkylene. In embodiments, the spacer is an unsubstituted C₃-C₁₈alkylene. In embodiments, the spacer is an unsubstituted linear C₃-C₁₅alkylene. In embodiments, the spacer is an unsubstituted linear C₆-C₂₁alkylene. In embodiments, the spacer is an unsubstituted linear C₉-C₂₁alkylene. In embodiments, the spacer is an unsubstituted linear C₉-C₁₈alkylene. In embodiments, the spacer is an unsubstituted linear C₉-C₁₅alkylene. In embodiments, the spacer is an unsubstituted linear C₁₂-C₁₅alkylene. In embodiments, the spacer is an unsubstituted linear C₁₂alkylene. In embodiments, the spacer is an unsubstituted linear C₁₃alkylene. In embodiments, the spacer is an unsubstituted linear C₁₄alkylene. In embodiments, the spacer is an unsubstituted linear C₁₅alkylene. A STAT3-binding nucleic acid (e.g. DNA) sequence orSTAT-binding nucleic acid (e.g. DNA) sequence is a nucleic acid (e.g.DNA) including phosphodiester linkages, phosphodiester derivativelinkages, and/or nucleic acid analogs, capable of binding STAT3 or aSTAT transcription factor respectively. In embodiments, the spacer is asubstituted 2 to 40 membered heteroalkylene. In embodiments, the spaceris a substituted 10 to 50 membered heteroalkylene. In embodiments, thespacer is a substituted 20 to 40 membered heteroalkylene. Inembodiments, the spacer is a substituted 25 to 40 memberedheteroalkylene. In embodiments, the spacer is a substituted 30 to 40membered heteroalkylene. In embodiments, the spacer is a substitutedliner 2 to 40 membered heteroalkylene. In embodiments, the spacer is asubstituted liner 10 to 50 membered heteroalkylene. In embodiments, thespacer is a substituted liner 20 to 40 membered heteroalkylene. Inembodiments, the spacer is a substituted liner 25 to 40 memberedheteroalkylene. In embodiments, the spacer is a substituted liner 30 to40 membered heteroalkylene.

In embodiments, the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent) preferentially binds phosphorylated STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) over unphosphorylatedSTAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). Inembodiments, the first STAT-binding nucleic acid sequence (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsequence) and second STAT-binding nucleic acid sequence (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsequence) form a double-stranded STAT-binding nucleic acid sequence(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid sequence). In embodiments, the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent) includes a STAT-binding nucleicacid sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid sequence) covalently bonded to a terminalmoiety. In embodiments, the STAT-binding nucleic acid substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent) binds phosphorylated STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments, theSTAT3-binding nucleic acid substituent binds STAT3 phosphorylated ontyrosine 705. In embodiments, the STAT-binding nucleic acid substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent) binds a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) phosphorylated on STAT1Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694,STAT6 Y641, or a residue corresponding to one of those residues. Inembodiments, the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent) binds human STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). In embodiments, the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent) binds STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) dimers. Inembodiments, the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent) binds dimers of phosphorylated STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof) (e.g.phosphorylated on STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693,STAT5A Y694, STAT5B Y694, STAT6 Y641, or a residue corresponding to oneof those residues). In embodiments, the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent) binds activated STAT (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments,the STAT-binding nucleic acid substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acid substituent)includes the nucleic acid sequence recognized by a STAT transcriptionfactor (e.g. apo-STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6), activated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6), phosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) (e.g. phosphorylated on STAT1 Y701, STAT2,Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or aresidue corresponding to one of those residues), or STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof)dimers). In embodiments, the STAT-binding nucleic acid substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent) includes the nucleic acid sequence contactedby a STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) that is associated with STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) transcriptional activationactivity). In embodiments, the STAT-binding nucleic acid substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent) includes a STAT-binding derivative of thenucleic acid sequence recognized by a STAT transcription factor (e.g.apo-STAT3, activated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6), phosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) (e.g. phosphorylated on STAT1 Y701, STAT2,Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6 Y641, or aresidue corresponding to one of those residues), or STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, or combinations thereof)dimers). In embodiments, the STAT-binding nucleic acid substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent) includes a STAT-binding derivative of thenucleic acid sequence contacted by a STAT transcription factor andassociated with STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) transcriptional activation activity). In embodiments, theSTAT-binding derivative of the nucleic acid sequence recognized by aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50) nucleotide substitutions (e.g. A, C, G, or Tsubstituted with a different nucleotide). In embodiments, theSTAT-binding derivative of the nucleic acid sequence recognized by aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50) internucleotide linkage replacements (e.g.phosphodiester replaced with a phosphodiester derivative or aphosphodiester derivative replaced with a phosphodiester). Inembodiments, the STAT-binding derivative of the nucleic acid sequencerecognized by a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, or 30) nucleotide deletions. In embodiments, theSTAT-binding derivative of the nucleic acid sequence recognized by aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81,82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99,or 100) nucleotide additions.

In embodiments, the spacer includes a first single DNA strand connectedto the first STAT3-binding DNA sequence and a second single DNA strandconnected to the second STAT3-binding DNA sequence, wherein the firstDNA strand includes a DNA sequence that is complementary to a DNAsequence included in the second single DNA strand (both single DNAstrands including their respective complementary sequences beingcollectively a “hybridized DNA overhang”. In embodiments, the spacerincludes a first single DNA strand connected to the first STAT-bindingDNA sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence) and a second single DNA strand connected tothe STAT-binding DNA sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA sequence), wherein the first DNAstrand includes a DNA sequence that is complementary to a DNA sequenceincluded in the second single DNA strand (both single DNA strandsincluding their respective complementary sequences being collectively a“hybridized DNA overhang”. In embodiments, the hybridized DNA overhangis 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or 100 base pairs long. In embodiments,the complementary DNA sequence in the hybridized DNA overhang is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100 base pairs long. A STAT3-binding DNA sequenceor STAT-binding DNA sequence is a DNA including phosphodiester linkages,phosphodiester derivative linkages, and/or nucleic acid analogs, capableof binding STAT3 or a STAT transcription factor respectively.

In embodiments, the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent)preferentially binds phosphorylated STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) over unphosphorylated STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments, thefirst STAT-binding DNA sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA sequence) and second STAT-bindingDNA sequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence) form a double-stranded STAT-binding DNAsequence (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA sequence). In embodiments, the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent) includes a STAT-binding DNA sequence(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingDNA sequence) covalently bonded to a terminal moiety. In embodiments,the STAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA substituent) binds phosphorylatedSTAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). Inembodiments, the STAT3-binding DNA substituent binds STAT3phosphorylated on tyrosine 705. In embodiments, the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent) binds a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) phosphorylated onSTAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5BY694, STAT6 Y641, or a residue corresponding to one of those residues.In embodiments, the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent)binds human STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, orSTAT6). In embodiments, the STAT-binding DNA substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNAsubstituent) binds STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, STAT6, or combinations thereof) dimers. In embodiments, theSTAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA substituent) binds dimers ofphosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,STAT6, or combinations thereof) (e.g. phosphorylated on STAT1 Y701,STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5B Y694, STAT6Y641, or a residue corresponding to one of those residues). Inembodiments, the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent)binds activated STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6). In embodiments, the STAT-binding DNA substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNAsubstituent) includes the DNA sequence recognized by a STATtranscription factor (e.g. apo-STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6), activated STAT (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6), phosphorylated STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) (e.g. phosphorylated onSTAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693, STAT5A Y694, STAT5BY694, STAT6 Y641, or a residue corresponding to one of those residues),or STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, STAT6, orcombinations thereof) dimers). In embodiments, the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent) includes the DNA sequence contacted by aSTAT transcription factor associated with STAT (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) transcriptional activationactivity). In embodiments, the STAT-binding DNA substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNAsubstituent) includes a STAT-binding derivative of the DNA sequencerecognized by a STAT transcription factor (e.g. apo-STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6), activated STAT (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6), phosphorylatedSTAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) (e.g.phosphorylated on STAT1 Y701, STAT2, Y690, STAT3 Y705, STAT4 Y693,STAT5A Y694, STAT5B Y694, STAT6 Y641, or a residue corresponding to oneof those residues), or STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, STAT6, or combinations thereof) dimers). In embodiments, theSTAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA substituent) includes aSTAT-binding derivative of the DNA sequence contacted by a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) associated with STAT (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) transcriptional activation activity). In embodiments,the STAT-binding derivative (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding derivative) of the DNA sequencerecognized by a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotide substitutions (e.g. A,C, G, or T substituted with a different nucleotide). In embodiments, theSTAT-binding derivative (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding derivative) of the DNA sequence recognized bya STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, or 50) internucleotide linkage replacements (e.g.phosphodiester replaced with a phosphodiester derivative or aphosphodiester derivative replaced with a phosphodiester). Inembodiments, the STAT-binding derivative (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding derivative) of the DNAsequence recognized by a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) includes one or more (e.g. 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, or 30) nucleotide deletions. In embodiments,the STAT-binding derivative (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding derivative) of the DNA sequencerecognized by a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) includes one or more (e.g. 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77,78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95,96, 97, 98, 99, or 100) nucleotide additions.

A terminal moiety is a chemically reactive moiety, detectable moiety,therapeutic moiety (e.g. anti-cancer agent or anti-viral agent), nucleicacid sequence, DNA sequence, substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. Inembodiments, a terminal moiety is a chemically reactive moiety,detectable moiety, therapeutic moiety (e.g. anti-cancer agent oranti-viral agent), nucleic acid sequence, DNA sequence, nucleic acidanalogs, R¹-substituted or unsubstituted alkyl, R¹-substituted orunsubstituted heteroalkyl, R¹-substituted or unsubstituted cycloalkyl,R¹-substituted or unsubstituted heterocycloalkyl, R¹-substituted orunsubstituted aryl, or R¹-substituted or unsubstituted heteroaryl. Inembodiments, a terminal moiety is a detectable moiety. In embodiments,the detectable moiety is a fluorescent dye, electron-dense reagent,enzyme, biotin, digoxigenin, paramagnetic molecule, paramagneticnanoparticle, contrast agent, magnetic resonance contrast agent, X-raycontrast agent, Gadolinium, radioisotope, radionuclide,fluorodeoxyglucose, gamma ray emitting radionuclide, positron-emittingradionuclide, biocolloid, microbubble, iodinated contrast agent, bariumsulfate, thorium dioxide, gold, gold nanoparticle, gold nanoparticleaggregate, fluorophore, two-photon fluorophore, hapten, protein, orfluorescent moiety. In embodiments, a terminal moiety is a therapeuticmoiety (e.g. anti-cancer agent or anti-viral agent).

In embodiments, the terminal moiety is a substituted or unsubstitutedalkyl, substituted or unsubstituted heteroalkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl. In embodiments, the terminal moiety is a substituted orunsubstituted C₁-C₄₀ alkyl, substituted or unsubstituted 2 to 40membered heteroalkyl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted 3 to 8 membered heterocycloalkyl,substituted or unsubstituted C₆-C₁₀ aryl, or substituted orunsubstituted 5 to 10 membered heteroaryl. In embodiments, the terminalmoiety is a substituted C₁-C₄₀ alkyl, substituted 2 to 40 memberedheteroalkyl, substituted C₃-C₈ cycloalkyl, substituted 3 to 8 memberedheterocycloalkyl, substituted C₆-C₁₀ aryl, or substituted 5 to 10membered heteroaryl. In embodiments, the terminal moiety is anR¹-substituted C₁-C₄₀ alkyl, R¹-substituted 2 to 40 memberedheteroalkyl, R¹-substituted C₃-C₈ cycloalkyl, R¹-substituted 3 to 8membered heterocycloalkyl, R¹-substituted C₆-C₁₀ aryl, or R¹-substituted5 to 10 membered heteroaryl. In embodiments, the terminal moiety is anR¹-substituted C₁-C₄₀ alkyl. In embodiments, the terminal moiety is an-(unsubstituted C₁-C₄₀ alkylene)-R¹. In embodiments, the terminal moietyis an -(unsubstituted linear C₁-C₄₀ alkylene)-R¹. In embodiments, theterminal moiety is an -(unsubstituted C₃-C₂₁ alkylene)-R¹. Inembodiments, the terminal moiety is an -(unsubstituted C₃-C₁₈alkylene)-R¹. In embodiments, the terminal moiety is an -(unsubstitutedlinear C₃-C₁₅ alkylene)-R¹. In embodiments, the terminal moiety is an-(unsubstituted linear C₆-C₂₁ alkylene)-R¹. In embodiments, the terminalmoiety is an -(unsubstituted linear C₉-C₂₁ alkylene)-R¹. In embodiments,the terminal moiety is an -(unsubstituted linear C₉-C₁₈ alkylene)-R¹. Inembodiments, the terminal moiety is an -(unsubstituted linear C₉-C₁₅alkylene)-R¹. In embodiments, the terminal moiety is an -(unsubstitutedlinear C₁₂-C₁₅ alkylene)-R¹. In embodiments, the terminal moiety is an-(unsubstituted linear C₁₂ alkylene)-R¹. In embodiments, the terminalmoiety is an -(unsubstituted linear C₁₃ alkylene)-R¹. In embodiments,the terminal moiety is an -(unsubstituted linear C₁₄ alkylene)-R¹. Inembodiments, the terminal moiety is an -(unsubstituted linear C_(is)alkylene)-R¹. In embodiments, the terminal moiety is an R¹-substituted 2to 40 membered heteroalkyl. In embodiments, the terminal moiety is an-(unsubstituted 2 to 40 membered heteroalkylene)-R¹. In embodiments, theterminal moiety is a -(substituted linear 2 to 40 memberedheteroalkylene)-R¹. In embodiments, the terminal moiety is a-(substituted 5 to 40 membered heteroalkylene)-R¹. In embodiments, theterminal moiety is a -(substituted 10 to 40 membered heteroalkylene)-R¹.In embodiments, the terminal moiety is a -(substituted 15 to 40 memberedheteroalkylene)-R¹. In embodiments, the terminal moiety is a-(substituted 20 to 40 membered heteroalkylene)-R¹. In embodiments, theterminal moiety is a -(substituted 30 to 40 membered heteroalkylene)-R¹.In embodiments, the terminal moiety is a -(substituted 2 to 35 memberedheteroalkylene)-R¹. In embodiments, the terminal moiety is a-(substituted 2 to 30 membered heteroalkylene)-R¹. In embodiments, theterminal moiety is a -(substituted 2 to 25 membered heteroalkylene)-R¹.In embodiments, the terminal moiety is a -(substituted 2 to 20 memberedheteroalkylene)-R¹. In embodiments, the terminal moiety is a-(substituted 2 to 10 membered heteroalkylene)-R¹. In embodiments, theterminal moiety is a -(substituted 2 to 50 membered heteroalkylene)-R¹.In embodiments, the terminal moiety is a -(substituted 2 to 60 memberedheteroalkylene)-R¹. In embodiments, the terminal moiety is a substituted2 to 40 membered heteroalkyl. In embodiments, the terminal moiety is asubstituted 10 to 50 membered heteroalkyl. In embodiments, the terminalmoiety is a substituted 20 to 40 membered heteroalkyl. In embodiments,the terminal moiety is a substituted 25 to 40 membered heteroalkyl. Inembodiments, the terminal moiety is a substituted 30 to 40 memberedheteroalkyl.

In embodiments, R¹ is a detectable moiety or a therapeutic moiety. Inembodiments, R¹ is a detectable moiety. In embodiments, the detectablemoiety is a fluorescent dye, electron-dense reagent, enzyme, biotin,digoxigenin, paramagnetic molecule, paramagnetic nanoparticle, contrastagent, magnetic resonance contrast agent, X-ray contrast agent,Gadolinium, radioisotope, radionuclide, fluorodeoxyglucose, gamma rayemitting radionuclide, positron-emitting radionuclide, biocolloid,microbubble, iodinated contrast agent, barium sulfate, thorium dioxide,gold, gold nanoparticle, gold nanoparticle aggregate, fluorophore,two-photon fluorophore, hapten, protein, or fluorescent moiety. Inembodiments, R¹ is a therapeutic moiety (e.g. anti-cancer agent oranti-viral agent). In embodiments, R¹ is H. In embodiments, R¹ is oxo.In embodiments, R¹ is oxygen. In embodiments, R¹ is sulfur. Inembodiments, R¹ is ═S.

In embodiments, the compound includes a linker between the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent and the STAT-binding nucleic acid substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent). In embodiments, the compound includes alinker between the TLR9-binding DNA substituent and the STAT3-bindingnucleic acid substituent. In embodiments, the compound includes a linkerbetween the TLR9-binding nucleic acid substituent and the STAT-bindingDNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-,or STAT6-binding DNA substituent). In embodiments, the STAT-bindingnucleic acid substituent is a STAT1-binding nucleic acid substituent. Inembodiments, the STAT-binding nucleic acid substituent is aSTAT2-binding nucleic acid substituent. In embodiments, the STAT-bindingnucleic acid substituent is a STAT3-binding nucleic acid substituent. Inembodiments, the STAT-binding nucleic acid substituent is aSTAT4-binding nucleic acid substituent. In embodiments, the STAT-bindingnucleic acid substituent is a STAT5A-binding nucleic acid substituent.In embodiments, the STAT-binding nucleic acid substituent is aSTAT5B-binding nucleic acid substituent. In embodiments, theSTAT-binding nucleic acid substituent is a STAT6-binding nucleic acidsubstituent.

In embodiments, the compound includes a linker between the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent and the STAT-binding DNA substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNAsubstituent). In embodiments, the compound includes a linker between theTLR9-binding DNA substituent and the STAT3-binding DNA substituent. Inembodiments, the compound includes a linker between the TLR9-binding DNAsubstituent and the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, the STAT-binding DNA substituent is a STAT1-binding DNAsubstituent. In embodiments, the STAT-binding DNA substituent is aSTAT2-binding DNA substituent. In embodiments, the STAT-binding DNAsubstituent is a STAT3-binding DNA substituent. In embodiments, theSTAT-binding DNA substituent is a STAT4-binding DNA substituent. Inembodiments, the STAT-binding DNA substituent is a STAT5A-binding DNAsubstituent. In embodiments, the STAT-binding DNA substituent is aSTAT5B-binding DNA substituent. In embodiments, the STAT-binding DNAsubstituent is a STAT6-binding DNA substituent.

A linker is a bond, nucleic acid sequence, two nucleic acid sequences,DNA sequence, two DNA sequences, nucleic acid analog sequence,substituted or unsubstituted alkylene, substituted or unsubstitutedheteroalkylene, substituted or unsubstituted cycloalkylene, substitutedor unsubstituted heterocycloalkylene, substituted or unsubstitutedarylene, or substituted or unsubstituted heteroarylene.

In embodiments, the linker is a substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene. In embodiments, the linkeris a substituted or unsubstituted C₁-C₂₀ alkylene, substituted orunsubstituted 2 to 20 membered heteroalkylene, substituted orunsubstituted C₃-C₈ cycloalkylene, substituted or unsubstituted 3 to 8membered heterocycloalkylene, substituted or unsubstituted C₆-C₁₀arylene, or substituted or unsubstituted 5 to 10 membered heteroarylene.In embodiments, the linker is an unsubstituted C₁-C₂₀ alkylene,unsubstituted 2 to 20 membered heteroalkylene, unsubstituted C₃-C₈cycloalkylene, unsubstituted 3 to 8 membered heterocycloalkylene,unsubstituted C₆-C₁₀ arylene, or unsubstituted 5 to 10 memberedheteroarylene. In embodiments, the linker is an unsubstituted C₁-C₂₀alkylene. In embodiments, the linker is a substituted or unsubstitutedC₁-C₄₀ alkylene, substituted or unsubstituted 2 to 40 memberedheteroalkylene, substituted or unsubstituted C₃-C₈ cycloalkylene,substituted or unsubstituted 3 to 8 membered heterocycloalkylene,substituted or unsubstituted C₆-C₁₀ arylene, or substituted orunsubstituted 5 to 10 membered heteroarylene. In embodiments, the linkeris a substituted or unsubstituted C₁-C₄₀ alkylene. In embodiments, thelinker is a substituted or unsubstituted 2 to 40 memberedheteroalkylene. In embodiments, the linker is a substituted 2 to 40membered heteroalkylene. In embodiments, the linker includes alkylphosphates (e.g., propyl phosphates). In embodiments, the linkerconsists of alkyl phosphates (e.g., propyl phosphates) bonded to thereminder of the compound by phosphates at both ends. In embodiments, thelinker consists of 1-6 alkyl phosphates (e.g., propyl phosphates) bondedto the remainder of the compound by phosphates on both ends. Inembodiments, the linker consists of 4-6 alkyl phosphates (e.g., propylphosphates) bonded to the remainder of the compound by phosphates onboth ends. In embodiments, the linker consists of 5 alkyl phosphates(e.g., propyl phosphates) bonded to the remainder of the compound byphosphates on both ends. A person having ordinary skill in the art willrecognize that a linker consisting of alkyl phosphates that is bonded tothe remainder of the compound by phosphates on both ends will have onemore phosphate than alkylene groups (e.g., a linker consisting of 4alkyl phosphates that is bonded to the reminder of the compound byphosphates at both ends will have five phosphates and four alkyl groupswith alternating phosphate groups and alkyl groups).

In embodiments, the linker includes a first single nucleic acid strandconnected to the TLR9-binding nucleic acid substituent and a secondsingle nucleic acid strand connected to the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent), wherein the first nucleic acidstrand includes a nucleic acid sequence that is complementary to anucleic acid sequence included in the second single nucleic acid strand(both single nucleic acid strands including their respectivecomplementary sequences being collectively a “hybridized nucleic acidoverhang”. In embodiments, the linker includes a first single nucleicacid strand connected to the TLR-binding nucleic acid (e.g. endosomalTLR-, TLR3-, TLR7-, TLR8-, or TLR9-binding nucleic acid) substituent anda second single nucleic acid strand connected to the STAT-bindingnucleic acid substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-,STAT5B-, or STAT6-binding nucleic acid substituent), wherein the firstnucleic acid strand includes a nucleic acid sequence that iscomplementary to a nucleic acid sequence included in the second singlenucleic acid strand (both single nucleic acid strands including theirrespective complementary sequences being collectively a “hybridizednucleic acid overhang”. In embodiments, the linker includes a firstsingle nucleic acid strand connected to the TLR9-binding nucleic acidsubstituent and a second single nucleic acid strand connected to theSTAT3-binding nucleic acid substituent, wherein the first nucleic acidstrand includes a nucleic acid sequence that is complementary to anucleic acid sequence included in the second single nucleic acid strand(both single nucleic acid strands including their respectivecomplementary sequences being collectively a “hybridized nucleic acidoverhang”. In embodiments, the hybridized nucleic acid overhang is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100 base pairs long. In embodiments, thecomplementary nucleic acid sequence in the hybridized nucleic acidoverhang is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100 base pairs long. Inembodiments, the first and second single nucleic acid strands in thehybridized nucleic acid overhang are complementary throughout theirentire lengths. In embodiments, the linker is an unsubstituted C₁-C₂₀alkylene. In embodiments, the linker is an unsubstituted linear C₁-C₂₀alkylene. In embodiments, the linker is an unsubstituted C₃-C₂₁alkylene. In embodiments, the linker is an unsubstituted C₃-C₁₈alkylene. In embodiments, the linker is an unsubstituted linear C₃-C₁₅alkylene. In embodiments, the linker is an unsubstituted linear C₆-C₂₁alkylene. In embodiments, the linker is an unsubstituted linear C₉-C₂₁alkylene. In embodiments, the linker is an unsubstituted linear C₉-C₁₈alkylene. In embodiments, the linker is an unsubstituted linear C₉-C₁₅alkylene. In embodiments, the linker is an unsubstituted linear C₁₂-C₁₅alkylene. In embodiments, the linker is an unsubstituted linear C₁₂alkylene. In embodiments, the linker is an unsubstituted linear C₁₃alkylene. In embodiments, the linker is an unsubstituted linear C₁₄alkylene. In embodiments, the linker is an unsubstituted linear C₁₅alkylene. In embodiments, the linker is a substituted 2 to 40 memberedheteroalkylene. In embodiments, the linker is a substituted 10 to 50membered heteroalkylene. In embodiments, the linker is a substituted 20to 40 membered heteroalkylene. In embodiments, the linker is asubstituted 25 to 40 membered heteroalkylene. In embodiments, the linkeris a substituted 30 to 40 membered heteroalkylene. In embodiments, thelinker is a substituted liner 2 to 40 membered heteroalkylene. Inembodiments, the linker is a substituted liner 10 to 50 memberedheteroalkylene. In embodiments, the linker is a substituted liner 20 to40 membered heteroalkylene. In embodiments, the linker is a substitutedliner 25 to 40 membered heteroalkylene. In embodiments, the linker is asubstituted liner 30 to 40 membered heteroalkylene.

In embodiments, the linker includes a first single DNA strand connectedto the TLR9-binding DNA substituent and a second single DNA strandconnected to the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent),wherein the first DNA strand includes a DNA sequence that iscomplementary to a DNA sequence included in the second single DNA strand(both single DNA strands including their respective complementarysequences being collectively a “hybridized DNA overhang”. Inembodiments, the linker includes a first single DNA strand connected tothe TLR-binding nucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-,or TLR9-binding nucleic acid) substituent and a second single DNA strandconnected to the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent),wherein the first DNA strand includes a DNA sequence that iscomplementary to a DNA sequence included in the second single DNA strand(both single DNA strands including their respective complementarysequences being collectively a “hybridized DNA overhang”. Inembodiments, the linker includes a first single DNA strand connected tothe TLR9-binding DNA substituent and a second single DNA strandconnected to the STAT3-binding DNA substituent, wherein the first DNAstrand includes a DNA sequence that is complementary to a DNA sequenceincluded in the second single DNA strand (both single DNA strandsincluding their respective complementary sequences being collectively a“hybridized DNA overhang”. In embodiments, the hybridized DNA overhangis 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or 100 base pairs long. In embodiments,the complementary DNA sequence in the hybridized DNA overhang is 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or 100 base pairs long. In embodiments, the firstand second single DNA strands in the hybridized DNA overhang arecomplementary throughout their entire lengths.

In embodiments, the compound includes a phosphodiester derivativelinkage (e.g., phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite linkages). In embodiments, thecompound includes a plurality of phosphodiester derivative linkages(e.g., phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, O-methylphosphoroamidite linkages, or combinationsthereof). In embodiments, the compound includes a phosphodiesterderivative linkage (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, or O-methylphosphoroamiditelinkages) in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphodiester derivative linkage (e.g.,phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite linkages) in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphodiester derivative linkage (e.g., phosphoramidate,phosphorodiamidate, phosphorothioate, phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, orO-methylphosphoroamidite linkages) in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a phosphodiesterderivative linkage (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, or O-methylphosphoroamiditelinkages) in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a phosphodiester derivativelinkage (e.g., phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite linkages), (e.g. 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24,25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96,97, 98, 99, or all internucleotide linkages in the compound arephosphodiester derivative linkages (e.g., phosphoramidate,phosphorodiamidate, phosphorothioate, phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate,O-methylphosphoroamidite linkages, or combinations thereof)). Inembodiments, the compound includes a phosphodiester derivative linkage(e.g., phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite linkages) in the STAT3-bindingDNA substituent. In embodiments, the compound includes a phosphodiesterderivative linkage (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, or O-methylphosphoroamiditelinkages) in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphodiester derivative linkage (e.g., phosphoramidate,phosphorodiamidate, phosphorothioate, phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, orO-methylphosphoroamidite linkages), (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, orall internucleotide linkages in the compound are phosphodiesterderivative linkages (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acids,phosphonocarboxylates, phosphonoacetic acid, phosphonoformic acid,methyl phosphonate, boron phosphonate, O-methylphosphoroamiditelinkages, or combinations thereof)).

In embodiments, the compound includes a phosphorothioate linkage. Inembodiments, the compound includes a plurality of phosphorothioatelinkages. In embodiments, the compound includes a phosphorothioatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphorothioate linkage in the TLR-binding nucleicacid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-binding nucleicacid) substituent. In embodiments, the compound includes aphosphorothioate linkage in the STAT3-binding nucleic acid substituent.In embodiments, the compound includes a phosphorothioate linkage in theSTAT-binding nucleic acid substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acid substituent). Inembodiments, one or more of the nucleic acid internucleotide linkages inthe compound is a phosphorothioate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound are phosphorothioatelinkages). In embodiments, the compound includes a phosphorothioatelinkage in the STAT3-binding DNA substituent. In embodiments, thecompound includes a phosphorothioate linkage in the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent). In embodiments, one or more of the DNAinternucleotide linkages in the compound is a phosphorothioate linkage(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkages in thecompound are phosphorothioate linkages).

In embodiments, the compound includes a phosphoramidate linkage. Inembodiments, the compound includes a plurality of phosphoramidatelinkages. In embodiments, the compound includes a phosphoramidatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphoramidate linkage in the TLR-binding nucleicacid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-binding nucleicacid) substituent. In embodiments, the compound includes aphosphoramidate linkage in the STAT3-binding nucleic acid substituent.In embodiments, the compound includes a phosphoramidate linkage in theSTAT-binding nucleic acid substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acid substituent). Inembodiments, one or more of the nucleic acid internucleotide linkages inthe compound is a phosphoramidate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound are phosphoramidatelinkages). In embodiments, the compound includes a phosphoramidatelinkage in the STAT3-binding DNA substituent. In embodiments, thecompound includes a phosphoramidate linkage in the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent). In embodiments, one or more of the DNAinternucleotide linkages in the compound is a phosphoramidate linkage(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkages in thecompound are phosphoramidate linkages).

In embodiments, the compound includes a phosphorodiamidate linkage. Inembodiments, the compound includes a plurality of phosphorodiamidatelinkages. In embodiments, the compound includes a phosphorodiamidatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphorodiamidate linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphorodiamidate linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a phosphorodiamidatelinkage in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a phosphorodiamidate linkage(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkages in thecompound are phosphorodiamidate linkages). In embodiments, the compoundincludes a phosphorodiamidate linkage in the STAT3-binding DNAsubstituent. In embodiments, the compound includes a phosphorodiamidatelinkage in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphorodiamidate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound arephosphorodiamidate linkages).

In embodiments, the compound includes a phosphorodithioate linkage. Inembodiments, the compound includes a plurality of phosphorodithioatelinkages. In embodiments, the compound includes a phosphorodithioatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphorodithioate linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphorodithioate linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a phosphorodithioatelinkage in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a phosphorodithioate linkage(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkages in thecompound are phosphorodithioate linkages). In embodiments, the compoundincludes a phosphorodithioate linkage in the STAT3-binding DNAsubstituent. In embodiments, the compound includes a phosphorodithioatelinkage in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphorodithioate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound arephosphorodithioate linkages).

In embodiments, the compound includes a phosphonocarboxylic acidlinkage. In embodiments, the compound includes a plurality ofphosphonocarboxylic acid linkages. In embodiments, the compound includesa phosphonocarboxylic acid linkage in the TLR9-binding DNA substituent.In embodiments, the compound includes a phosphonocarboxylic acid linkagein the TLR-binding nucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-,TLR8-, or TLR9-binding nucleic acid) substituent. In embodiments, thecompound includes a phosphonocarboxylic acid linkage in theSTAT3-binding nucleic acid substituent. In embodiments, the compoundincludes a phosphonocarboxylic acid linkage in the STAT-binding nucleicacid substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-,or STAT6-binding nucleic acid substituent). In embodiments, one or moreof the nucleic acid internucleotide linkages in the compound is aphosphonocarboxylic acid linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, orall internucleotide linkages in the compound are phosphonocarboxylicacid linkages). In embodiments, the compound includes aphosphonocarboxylic acid linkage in the STAT3-binding DNA substituent.In embodiments, the compound includes a phosphonocarboxylic acid linkagein the STAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphonocarboxylic acid linkage (e.g. 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or all internucleotide linkages in the compound arephosphonocarboxylic acid linkages).

In embodiments, the compound includes a phosphonocarboxylate linkage. Inembodiments, the compound includes a plurality of phosphonocarboxylatelinkages. In embodiments, the compound includes a phosphonocarboxylatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphonocarboxylate linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphonocarboxylate linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes aphosphonocarboxylate linkage in the STAT-binding nucleic acidsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding nucleic acid substituent). In embodiments, one or more ofthe nucleic acid internucleotide linkages in the compound is aphosphonocarboxylate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47,48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65,66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83,84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or allinternucleotide linkages in the compound are phosphonocarboxylatelinkages). In embodiments, the compound includes a phosphonocarboxylatelinkage in the STAT3-binding DNA substituent. In embodiments, thecompound includes a phosphonocarboxylate linkage in the STAT-binding DNAsubstituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, orSTAT6-binding DNA substituent). In embodiments, one or more of the DNAinternucleotide linkages in the compound is a phosphonocarboxylatelinkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkagesin the compound are phosphonocarboxylate linkages).

In embodiments, the compound includes a phosphonoacetic acid linkage. Inembodiments, the compound includes a plurality of phosphonoacetic acidlinkages. In embodiments, the compound includes a phosphonoacetic acidlinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphonoacetic acid linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphonoacetic acid linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a phosphonoaceticacid linkage in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a phosphonoacetic acidlinkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkagesin the compound are phosphonoacetic acid linkages). In embodiments, thecompound includes a phosphonoacetic acid linkage in the STAT3-bindingDNA substituent. In embodiments, the compound includes a phosphonoaceticacid linkage in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphonoacetic acid linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound are phosphonoaceticacid linkages).

In embodiments, the compound includes a phosphonoformic acid linkage. Inembodiments, the compound includes a plurality of phosphonoformic acidlinkages. In embodiments, the compound includes a phosphonoformic acidlinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a phosphonoformic acid linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes aphosphonoformic acid linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a phosphonoformicacid linkage in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a phosphonoformic acidlinkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71,72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkagesin the compound are phosphonoformic acid linkages). In embodiments, thecompound includes a phosphonoformic acid linkage in the STAT3-bindingDNA substituent. In embodiments, the compound includes a phosphonoformicacid linkage in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a phosphonoformic acid linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound are phosphonoformicacid linkages).

In embodiments, the compound includes a methyl phosphonate linkage. Inembodiments, the compound includes a plurality of methyl phosphonatelinkages. In embodiments, the compound includes a methyl phosphonatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a methyl phosphonate linkage in the TLR-bindingnucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-bindingnucleic acid) substituent. In embodiments, the compound includes amethyl phosphonate linkage in the STAT3-binding nucleic acidsubstituent. In embodiments, the compound includes a methyl phosphonatelinkage in the STAT-binding nucleic acid substituent (e.g. STAT1-,STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acidsubstituent). In embodiments, one or more of the nucleic acidinternucleotide linkages in the compound is a methyl phosphonate linkage(e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91,92, 93, 94, 95, 96, 97, 98, 99, or all internucleotide linkages in thecompound are methyl phosphonate linkages). In embodiments, the compoundincludes a methyl phosphonate linkage in the STAT3-binding DNAsubstituent. In embodiments, the compound includes a methyl phosphonatelinkage in the STAT-binding DNA substituent (e.g. STAT1-, STAT2-,STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-binding DNA substituent). Inembodiments, one or more of the DNA internucleotide linkages in thecompound is a methyl phosphonate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62,63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80,81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98,99, or all internucleotide linkages in the compound are methylphosphonate linkages).

In embodiments, the compound includes a boron phosphonate linkage. Inembodiments, the compound includes a plurality of boron phosphonatelinkages. In embodiments, the compound includes a boron phosphonatelinkage in the TLR9-binding DNA substituent. In embodiments, thecompound includes a boron phosphonate linkage in the TLR-binding nucleicacid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, or TLR9-binding nucleicacid) substituent. In embodiments, the compound includes a boronphosphonate linkage in the STAT3-binding nucleic acid substituent. Inembodiments, the compound includes a boron phosphonate linkage in theSTAT-binding nucleic acid substituent (e.g. STAT1-, STAT2-, STAT3-,STAT4-, STAT5A-, STAT5B-, or STAT6-binding nucleic acid substituent). Inembodiments, one or more of the nucleic acid internucleotide linkages inthe compound is a boron phosphonate linkage (e.g. 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61,62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79,80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97,98, 99, or all internucleotide linkages in the compound are boronphosphonate linkages). In embodiments, the compound includes a boronphosphonate linkage in the STAT3-binding DNA substituent. Inembodiments, the compound includes a boron phosphonate linkage in theSTAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA substituent). In embodiments, oneor more of the DNA internucleotide linkages in the compound is a boronphosphonate linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or allinternucleotide linkages in the compound are boron phosphonatelinkages).

In embodiments, the compound includes an O-methylphosphoroamiditelinkage. In embodiments, the compound includes a plurality ofO-methylphosphoroamidite linkages. In embodiments, the compound includesan O-methylphosphoroamidite linkage in the TLR9-binding DNA substituent.In embodiments, the compound includes an O-methylphosphoroamiditelinkage in the TLR-binding nucleic acid (e.g. endosomal TLR-, TLR3-,TLR7-, TLR8-, or TLR9-binding nucleic acid) substituent. In embodiments,the compound includes an O-methylphosphoroamidite linkage in theSTAT3-binding nucleic acid substituent. In embodiments, the compoundincludes an O-methylphosphoroamidite linkage in the STAT-binding nucleicacid substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-,or STAT6-binding nucleic acid substituent). In embodiments, one or moreof the nucleic acid internucleotide linkages in the compound is aO-methylphosphoroamidite linkage (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, orall internucleotide linkages in the compound areO-methylphosphoroamidite linkages). In embodiments, the compoundincludes an O-methylphosphoroamidite linkage in the STAT3-binding DNAsubstituent. In embodiments, the compound includes anO-methylphosphoroamidite linkage in the STAT-binding DNA substituent(e.g. STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingDNA substituent). In embodiments, one or more of the DNA internucleotidelinkages in the compound is a O-methylphosphoroamidite linkage (e.g. 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39,40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57,58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93,94, 95, 96, 97, 98, 99, or all internucleotide linkages in the compoundare O-methylphosphoroamidite linkages).

In embodiments, the compound includes a nucleic acid analog (e.g. LNA).In embodiments, the compound includes a plurality of nucleic acidanalogs (e.g. LNA). In embodiments, the compound includes a nucleic acidanalog (e.g. LNA) in the TLR9-binding DNA substituent. In embodiments,the compound includes a nucleic acid analog (e.g. LNA) in theTLR-binding nucleic acid (e.g. endosomal TLR-, TLR3-, TLR7-, TLR8-, orTLR9-binding nucleic acid) substituent. In embodiments, the compoundincludes a nucleic acid analog (e.g. LNA) in the STAT3-binding nucleicacid substituent. In embodiments, the compound includes a nucleic acidanalog (e.g. LNA) in the STAT-binding nucleic acid substituent (e.g.STAT1-, STAT2-, STAT3-, STAT4-, STAT5A-, STAT5B-, or STAT6-bindingnucleic acid substituent). In embodiments, one or more of the nucleicacids in the compound is a nucleic acid analog (e.g. LNA) (e.g. 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22,23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76,77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94,95, 96, 97, 98, 99, or all nucleic acids in the compound are nucleicacid analogs (e.g. LNA)). In embodiments, the compound includes anucleic acid analog (e.g. LNA) in the STAT3-binding DNA substituent. Inembodiments, the compound includes a nucleic acid analog (e.g. LNA) inthe STAT-binding DNA substituent (e.g. STAT1-, STAT2-, STAT3-, STAT4-,STAT5A-, STAT5B-, or STAT6-binding DNA substituent). In embodiments, oneor more of the DNA nucleic acids in the compound is a nucleic acidanalog (e.g. LNA) (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50,51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68,69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86,87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or all nucleic acidsin the compound are nucleic acid analogs (e.g. LNA)).

TABLE 1 STAT-binding nucleic acid substituent/ TLR-binding nucleicEndosomal acid substituent TLR TLR TLR3 TLR7 TLR8 TLR9 STAT 1 2 3 4 5 6STAT1 7 8 9 10 11 12 STAT2 13 14 15 16 17 18 STAT3 19 20 21 22 23 24STAT4 25 26 27 28 29 30 STAT5A 31 32 33 34 35 36 STAT5B 37 38 39 40 4142 STAT6 43 44 45 46 47 48

In embodiments, the compound includes a combination of a STAT-bindingnucleic acid substituent and TLR-binding nucleic acid substituent,selected from the combinations in Table 1 immediately above. Inembodiments the STAT-binding nucleic acid substituent and TLR-bindingnucleic acid substituent are as described herein. In embodiments theSTAT-binding nucleic acid substituent and TLR-binding nucleic acidsubstituent are human. In embodiments the STAT-binding nucleic acidsubstituent is a STAT-binding DNA substituent. In embodiments theTLR-binding nucleic acid substituent is a TLR-binding DNA substituent.

In embodiments, the spacer is a substituted or unsubstitutedalkylphosphate spacer having the structure -L¹-(PO₄H-L²)_(n)-, whereinL¹ and L² are independently a substituted or unsubstituted alkylene(e.g. substituted or unsubstituted C₁-C₁₀ alkylene). In embodiments,wherein L¹ and L² are independently a unsubstituted alkylene (e.g.unsubstituted C₁-C₁₀ alkylene). In embodiments, wherein L¹ and L² areunsubstituted C₃ alkylene. In embodiments, L¹ and L² are the same. Thesymbol n is an integer from 1 to 500. In embodiments, n is an integerfrom 1 to 400. In embodiments, n is an integer from 1 to 300. Inembodiments, n is an integer from 1 to 200. In embodiments, n is aninteger from 1 to 100. In embodiments, n is an integer from 1 to 50. Inembodiments, n is an integer from 1 to 25. In embodiments, n is aninteger from 1 to 10. In embodiments, n is an integer from 1 to 5. Inembodiments, n is an integer from 1 to 4. A person having ordinary skillin the art will recognize that the substituted or unsubstitutedalkylphosphate spacer may exist in its salt form, e.g. L¹-(PO₄⁻-L²)_(n)-. The substituted or unsubstituted alkylphosphate spacer mayconnect the 3′ phosphate of a first nucleic acid to a 5′ phosphate of asecond nucleic acid as described herein. In embodiments, the spacer maybe a —(CH₂CH₂CH₂—PO₄H)_(n)—, wherein n is an integer between 1 and 20(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20). In embodiments, the spacer may be a —(CH₂CH₂CH₂—PO₄H)_(n)—,wherein n is an integer between 1 and 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) wherein the terminalspacer propyl moiety is bonded directly to a 3′ phosphate moiety and theterminal spacer phosphate moiety is bonded directly to a 5′ carbon of adeoxyribose. In embodiments, the spacer includes a phosphodiesterderivative linkage (e.g., phosphoramidate linkage, phosphorodiamidatelinkage, phosphorothioate linkage, phosphorodithioate linkage,phosphonocarboxylic acid linkage, phosphonocarboxylate linkage,phosphonoacetic acid linkage, phosphonoformic acid linkage, methylphosphonate linkage, boron phosphonate linkage, orO-methylphosphoroamidite linkage). In embodiments, the spacer includes aphosphodiester derivative (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acid,phosphonocarboxylate, phosphonoacetic acid, phosphonoformic acid, methylphosphonate, boron phosphonate, and O-methylphosphoroamidite).

In embodiments, the linker is a substituted or unsubstitutedalkylphosphate linker having the structure -L^(1a)-(PO₄H-L^(2a))_(n1)-,wherein L^(1a) and L^(2a) are independently a substituted orunsubstituted alkylene (e.g. substituted or unsubstituted C₁-C₁₀alkylene). In embodiments, wherein L^(1a) and L^(2a) are independently aunsubstituted alkylene (e.g. unsubstituted C₁-C₁₀ alkylene). Inembodiments, wherein L^(1a) and L^(2a) are unsubstituted C₃ alkylene. Inembodiments, L^(1a) and L^(2a) are the same. The symbol n1 is an integerfrom 1 to 500. In embodiments, n1 is an integer from 1 to 400. Inembodiments, n1 is an integer from 1 to 300. In embodiments, n1 is aninteger from 1 to 200. In embodiments, n1 is an integer from 1 to 100.In embodiments, n1 is an integer from 1 to 50. In embodiments, n1 is aninteger from 1 to 25. In embodiments, n1 is an integer from 1 to 10. Inembodiments, n1 is an integer from 1 to 5. In embodiments, n1 is aninteger from 1 to 4. A person having ordinary skill in the art willrecognize that the substituted or unsubstituted alkylphosphate linkermay exist in its salt form, e.g. L^(1a)-(PO₄ ⁻-L^(2a))_(n1)-. Thesubstituted or unsubstituted alkylphosphate linker may connect the 3′phosphate of a first nucleic acid to a 5′ phosphate of a second nucleicacid as described herein. In embodiments, the linker is a—(CH₂CH₂CH₂—PO₄H)_(n1)—, wherein n1 is an integer between 1 and 20(e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,19, or 20). In embodiments, the linker is a —(CH₂CH₂CH₂—PO₄H)_(n1)—,wherein n1 is an integer between 1 and 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) wherein the terminallinker propyl moiety is bonded directly to a 3′ phosphate moiety and theterminal linker phosphate moiety is bonded directly to a 5′ carbon of adeoxyribose. In embodiments, the linker includes a phosphodiesterderivative linkage (e.g., phosphoramidate linkage, phosphorodiamidatelinkage, phosphorothioate linkage, phosphorodithioate linkage,phosphonocarboxylic acid linkage, phosphonocarboxylate linkage,phosphonoacetic acid linkage, phosphonoformic acid linkage, methylphosphonate linkage, boron phosphonate linkage, orO-methylphosphoroamidite linkage). In embodiments, the linker includes aphosphodiester derivative (e.g., phosphoramidate, phosphorodiamidate,phosphorothioate, phosphorodithioate, phosphonocarboxylic acid,phosphonocarboxylate, phosphonoacetic acid, phosphonoformic acid, methylphosphonate, boron phosphonate, and O-methylphosphoroamidite).

In embodiments, the terminal moiety is a substituted or unsubstitutedalkylphosphate terminal moiety having the structure-L^(1b)-(PO₄H-L^(2b))_(n2)-H, wherein L^(1b) and L^(2b) areindependently a substituted or unsubstituted alkylene (e.g. substitutedor unsubstituted C₁-C₁₀ alkylene). In embodiments, wherein L^(1b) andL^(2b) are independently a unsubstituted alkylene (e.g. unsubstitutedC₁-C₁₀ alkylene). In embodiments, wherein L^(1b) and L^(2b) areunsubstituted C₃ alkylene. In embodiments, L^(1b) and L^(2b) are thesame. The symbol n2 is an integer from 1 to 500. In embodiments, n2 isan integer from 1 to 400. In embodiments, n2 is an integer from 1 to300. In embodiments, n2 is an integer from 1 to 200. In embodiments, n2is an integer from 1 to 100. In embodiments, n2 is an integer from 1 to50. In embodiments, n2 is an integer from 1 to 25. In embodiments, n2 isan integer from 1 to 10. In embodiments, n2 is an integer from 1 to 5.In embodiments, n2 is an integer from 1 to 4. A person having ordinaryskill in the art will recognize that the substituted or unsubstitutedalkylphosphate terminal moiety may exist in its salt form, e.g.L^(1b)-(PO₄ ⁻-L^(2b))_(n2)-H. The substituted or unsubstitutedalkylphosphate terminal moiety may connect to the 3′ phosphate of anucleic acid as described herein. In embodiments, the terminal moiety isa substituted or unsubstituted alkylphosphate terminal moiety having thestructure -L^(1b)-(PO₄H-L^(2b))_(n2)-PO₄H₂. A person having ordinaryskill in the art will recognize that the substituted or unsubstitutedalkylphosphate terminal moiety may exist in any of its salt forms, e.g.L^(1b)-(PO₄ ⁻-L^(2b))_(n2)-PO₄ ²⁻. In embodiments, the terminal moietyis a substituted or unsubstituted C₁-C₄₀ alkyl, substituted orunsubstituted 2 to 40 membered heteroalkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C₆-C₁₀ aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl. Inembodiments, the terminal moiety is a substituted or unsubstitutedC₁-C₄₀ alkyl. In embodiments, the terminal moiety is a substituted orunsubstituted 2 to 40 membered heteroalkyl. In embodiments, the terminalmoiety is a substituted 2 to 40 membered heteroalkyl. In embodiments,the terminal moiety includes alkyl phosphates (e.g., propyl phosphates).In embodiments, the terminal moiety consists of alkyl phosphates (e.g.,propyl phosphates) bonded to the reminder of the compound by phosphatesat both ends. In embodiments, the linker terminal moiety consists of 1-6alkyl phosphates (e.g., propyl phosphates). In embodiments, the terminalmoiety consists of 4-6 alkyl phosphates (e.g., propyl phosphates). Inembodiments, the terminal moiety consists of 5 alkyl phosphates (e.g.,propyl phosphates). In embodiments, the terminal moiety includes aterminal phosphate. In embodiments, the terminal moiety is a—(CH₂CH₂CH₂—PO₄H)_(n2)—CH₂CH₂CH₂CH₂CH₂CH₂NH₂, wherein n2 is an integerbetween 1 and 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20). In embodiments, the terminal moiety is a—(CH₂CH₂CH₂—PO₄H)_(n2)—CH₂CH₂CH₂CH₂CH₂CH₂NH₂, wherein n2 is an integerbetween 1 and 20 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, or 20) wherein the terminal moiety propyl moiety atthe terminus is bonded directly to a 3′ phosphate moiety. Inembodiments, the terminal moiety includes a phosphodiester derivativelinkage (e.g., phosphoramidate linkage, phosphorodiamidate linkage,phosphorothioate linkage, phosphorodithioate linkage,phosphonocarboxylic acid linkage, phosphonocarboxylate linkage,phosphonoacetic acid linkage, phosphonoformic acid linkage, methylphosphonate linkage, boron phosphonate linkage, orO-methylphosphoroamidite linkage). In embodiments, the terminal moietyincludes a phosphodiester derivative (e.g., phosphoramidate,phosphorodiamidate, phosphorothioate, phosphorodithioate,phosphonocarboxylic acid, phosphonocarboxylate, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate, andO-methylphosphoroamidite).

An example of a linker or spacer is shown below.

In embodiments, the compound is

G*G*TGCATCGATGCAGG*G*G*G*G-xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx3′ (SEQ ID NO:6), * is a phosphothioate linking group, x is an alkylphosphate, except for 3′ terminal x, which is an alkyl-amino followingthe final phosphate group). In embodiments, the phosphodiester linkageof the compound is replaced with a phosphodiester derivative linkage(e.g., phosphoramidate, phosphorodiamidate, phosphorothioate,phosphorodithioate, phosphonocarboxylic acids, phosphonocarboxylates,phosphonoacetic acid, phosphonoformic acid, methyl phosphonate, boronphosphonate, or O-methylphosphoroamidite linkages). In embodiments, aplurality of phosphodiester linkage of the compound are replaced with,phosphodiester derivative linkages (e.g., phosphoramidate,phosphorodiamidate, phosphorothioate, phosphorodithioate,phosphonocarboxylic acids, phosphonocarboxylates, phosphonoacetic acid,phosphonoformic acid, methyl phosphonate, boron phosphonate,O-methylphosphoroamidite linkages, or combinations thereof). Inembodiments, a phosphorothioate linkage of the compound is replaced witha phosphodiester linkage or a different phosphodiester derivativelinkage. In embodiments, a plurality of phosphorothioate linkages of thecompound are replaced with phosphodiester linkages or differentphosphodiester derivative linkages. In embodiments, a nucleobase (i.e.,cytosine, guanine, adenine, or thymine) of the compound is replaced witha different nucleobase (i.e., cytosine, guanine, adenine, or thymine).In embodiments, a plurality of nucleobases (i.e., cytosine, guanine,adenine, or thymine) of the compound are replaced with differentnucleobases (i.e., cytosine, guanine, adenine, or thymine). Inembodiments, the compound is covalently bound to a detectable moiety ortherapeutic moiety at the 3′ end of the terminal moiety. In embodiments,a propylene is replaced with a nucleoside (C, G, A, or T bound to deoxyribose).

In embodiments, R¹ is independently oxo, halogen, —CF₃, —CN, —OH, —COOH,—CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H, —SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂,—NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H, —NHC═(O)H, —NHC(O)—OH, —NHOH,—OCF₃, —OCHF₂, R⁴-substituted or unsubstituted alkyl, R⁴-substituted orunsubstituted heteroalkyl, R⁴-substituted or unsubstituted cycloalkyl,R⁴-substituted or unsubstituted heterocycloalkyl, R⁴-substituted orunsubstituted aryl, or R⁴-substituted or unsubstituted heteroaryl.

R⁴ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁵-substituted orunsubstituted alkyl, R⁵-substituted or unsubstituted heteroalkyl,R⁵-substituted or unsubstituted cycloalkyl, R⁵-substituted orunsubstituted heterocycloalkyl, R⁵-substituted or unsubstituted aryl, orR⁵-substituted or unsubstituted heteroaryl.

R⁵ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁶-substituted orunsubstituted alkyl, R⁶-substituted or unsubstituted heteroalkyl,R⁶-substituted or unsubstituted cycloalkyl, R⁶-substituted orunsubstituted heterocycloalkyl, R⁶-substituted or unsubstituted aryl, orR⁶-substituted or unsubstituted heteroaryl.

In embodiments, a spacer is a bond, nucleic acid sequence, DNA sequence,nucleic acid analog sequence, R²-substituted or unsubstituted alkylene,R²-substituted or unsubstituted heteroalkylene, R²-substituted orunsubstituted cycloalkylene, R²-substituted or unsubstitutedheterocycloalkylene, R²-substituted or unsubstituted arylene, orR²-substituted or unsubstituted heteroarylene.

In embodiments, R² is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁷-substituted orunsubstituted alkyl, R⁷-substituted or unsubstituted heteroalkyl,R⁷-substituted or unsubstituted cycloalkyl, R⁷-substituted orunsubstituted heterocycloalkyl, R⁷-substituted or unsubstituted aryl, orR⁷-substituted or unsubstituted heteroaryl.

R⁷ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁸-substituted orunsubstituted alkyl, R⁸-substituted or unsubstituted heteroalkyl,R⁸-substituted or unsubstituted cycloalkyl, R⁸-substituted orunsubstituted heterocycloalkyl, R⁸-substituted or unsubstituted aryl, orR⁸-substituted or unsubstituted heteroaryl.

R⁸ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R⁹-substituted orunsubstituted alkyl, R⁹-substituted or unsubstituted heteroalkyl,R⁹-substituted or unsubstituted cycloalkyl, R⁹-substituted orunsubstituted heterocycloalkyl, R⁹-substituted or unsubstituted aryl, orR⁹-substituted or unsubstituted heteroaryl.

In embodiments, a linker is a bond, nucleic acid sequence, DNA sequence,nucleic acid analog sequence, R³-substituted or unsubstituted alkylene,R³-substituted or unsubstituted heteroalkylene, R³-substituted orunsubstituted cycloalkylene, R³-substituted or unsubstitutedheterocycloalkylene, R³-substituted or unsubstituted arylene, orR³-substituted or unsubstituted heteroarylene.

In embodiments, R³ is independently, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R¹⁰-substituted orunsubstituted alkyl, R¹⁰-substituted or unsubstituted heteroalkyl,R¹⁰-substituted or unsubstituted cycloalkyl, R¹⁰-substituted orunsubstituted heterocycloalkyl, R¹⁰-substituted or unsubstituted aryl,or R¹⁰-substituted or unsubstituted heteroaryl.

R¹⁰ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R¹¹-substituted orunsubstituted alkyl, R¹¹-substituted or unsubstituted heteroalkyl,R¹¹-substituted or unsubstituted cycloalkyl, R¹¹-substituted orunsubstituted heterocycloalkyl, R¹¹-substituted or unsubstituted aryl,or R¹¹-substituted or unsubstituted heteroaryl.

R¹¹ is independently oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, R¹²-substituted orunsubstituted alkyl, R¹²-substituted or unsubstituted heteroalkyl,R¹²-substituted or unsubstituted cycloalkyl, R¹²-substituted orunsubstituted heterocycloalkyl, R¹²-substituted or unsubstituted aryl,or R¹²-substituted or unsubstituted heteroaryl.

R⁶, R⁹, and R¹² are independently hydrogen, oxo,

halogen, —CF₃, —CN, —OH, —NH₂, —COOH, —CONH₂, —NO₂, —SH, —SO₂Cl, —SO₃H,—SO₄H, —SO₂NH₂, —NHNH₂, —ONH₂, —NHC═(O)NHNH₂, —NHC═(O) NH₂, —NHSO₂H,—NHC═(O)H, —NHC(O)—OH, —NHOH, —OCF₃, —OCHF₂, unsubstituted alkyl,unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstitutedheterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl.

In some embodiments, a compound as described herein may include multipleinstances of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², and/orother variables. In such embodiments, each variable may optional bedifferent and be appropriately labeled to distinguish each group forgreater clarity. For example, where each R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, and/or R¹² is different, they may be referred to, forexample, as R^(1a), R^(1b), R^(1c), R^(1d), R^(1e), R^(1f), R^(1g),R^(1h), R^(1i), R^(1j), R^(1k), R^(1l), R^(1m), R^(1n), R^(1o), R^(1p),R^(1q), R^(1r), R^(1s), R^(1t), R^(1u), R^(1v), R^(1w), R^(2a), R^(2b),R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j), R^(2k),R^(2l), R^(2m), R^(2n), R^(2o), R^(2p), R^(2q), R^(2r), R^(2s), R^(2t),R^(2u), R^(2v), R^(2w), R^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R^(3f),R^(3g), R^(3h), R^(3i), R^(3j), R^(3k), R^(3l), R^(3m), R^(3n), R^(3o),R^(3p), R^(3q), R^(3r), R^(3s), R^(3t), R^(3u), R^(3v), R^(3w), R^(4a),R^(4b), R^(4c), R^(4d), R^(4e), R^(4f), R^(4g), R^(4h), R^(4i), R^(4j),R^(4k), R^(4l), R^(4m), R^(4n), R^(4o), R^(4p), R^(4q), R^(4r), R^(4s),R^(4t), R^(4u), R^(4v), R^(4w), R^(5a), R^(5b), R^(5c), R^(5d), R^(5e),R^(5f), R^(5g), R^(5h), R^(5i), R^(5j), R^(5k), R^(5l), R^(5m), R^(5n),R^(5o), R^(5p), R^(5q), R^(5r), R^(5s), R^(5t), R^(5u), R^(5v), R^(5w),R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), R^(6f), R^(6g), R^(6h), R^(6i),R^(6j), R^(6k), R^(6l), R^(6m), R^(6n), R^(6o), R^(6p), R^(6q), R^(6r),R^(6s), R^(6t), R^(6u), R^(6v), R^(6w), R^(7a), R^(7b), R^(7c), R^(7d),R^(7e), R^(7f), R^(7g), R^(7h), R^(7i), R^(7j), R^(7k), R^(7l), R^(7m),R^(7n), R^(7o), R^(7p), R^(7q), R^(7r), R^(7s), R^(7t), R^(7u), R^(7v),R^(7w), R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), R^(8h),R^(8i), R^(8j), R^(8k), R^(8l), R^(8m), R^(8n), R^(8o), R^(8p), R^(8q),R^(8r), R^(8s), R^(8t), R^(8u), R^(8v), R^(8w), R^(9a), R^(9b), R^(9c),R^(9d), R^(9e), R^(9f), R^(9g), R^(9h), R^(9i), R^(9j), R^(9k), R^(9l),R^(9m), R^(9n), R^(9o), R^(9p), R^(9q), R^(9r), R^(9s), R^(9t), R^(9u),R^(9v), R^(9w), R^(10a), R^(10b), R^(10c), R^(10d), R^(10e), R^(10f),R^(10g), R^(10h), R^(10i), R^(10j), R^(10k), R^(10l), R^(10m), R^(10n),R^(10o), R^(10p), R^(10q), R^(10r), R^(10s), R^(10t), R^(10u), R^(10v),R^(10w), R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), R^(11f), R^(11g),R^(11h), R^(11i), R^(11j), R^(11k), R^(11l), R^(11m), R^(11n), R^(11o),R^(11p), R^(11q), R^(11r), R^(11s), R^(11t), R^(11u), R^(11v), R^(11w),R^(12a), R^(12b), R^(12c), R^(12d), R^(12e), R^(12f), R^(12g), R^(12h),R^(12i), R^(12j), R^(12k), R^(12l), R^(12m), R^(12n), R^(12o), R^(12p),R^(12q), R^(12r), R^(12s), R^(12t), R^(12u), R^(12v), or R^(12w)respectively, wherein the definition of R¹ is assumed by R^(1a), R^(1b),R^(1c), R^(1d), R^(1e), R^(1f), R^(1g), R^(1h), R^(1i), R^(1j), R^(1k),R^(1l), R^(1m), R^(1n), R^(1o), R^(1p), R^(1q), R^(1r), R^(1s), R^(1t),R^(1u), R^(1v), R^(1w), the definition of R² is assumed by R^(2a),R^(2b), R^(2c), R^(2d), R^(2e), R^(2f), R^(2g), R^(2h), R^(2i), R^(2j),R^(2k), R^(2l), R^(2m), R^(2n), R^(2o), R^(2p), R^(2q), R^(2r), R^(2s),R^(2t), R^(2u), R^(2v), or R^(2w) the definition of R³ is assumed byR^(3a), R^(3b), R^(3c), R^(3d), R^(3e), R^(3f), R^(3g), R^(3h), R^(3i),R^(3j), R^(3k), R^(3l), R^(3m), R^(3n), R^(3o), R^(3p), R^(3q), R^(3r),R^(3s), R^(3t), R^(3u), R^(3v), R^(3w), the definition of R⁴ is assumedby R^(4a), R^(4b), R^(4c), R^(4d), R^(4e), R^(4f), R^(4g), R^(4h),R^(4i), R^(4j), R^(4k), R^(4l), R^(4m), R^(4n), R^(4o), R^(4p), R^(4q),R^(4r), R^(4s), R^(4t), R^(4u), R^(4v), R^(4w), the definition of R⁵ isassumed by R^(5a), R^(5b), R^(5c), R^(5d), R^(5e), R^(5f), R^(5g),R^(5h), R^(5i), R^(5j), R^(5k), R^(5l), R^(5m), R^(5n), R^(5o), R^(5p),R^(5q), R^(5r), R^(5s), R^(5t), R^(5u), R^(5v), R^(5w), the definitionof R⁶ is assumed by R^(6a), R^(6b), R^(6c), R^(6d), R^(6e), R^(6f),R^(6g), R^(6h), R^(6i), R^(6j), R^(6k), R^(6l), R^(6m), R^(6n), R^(6o),R^(6p), R^(6q), R^(6r), R^(6s), R^(6t), R^(6u), R^(6v), R^(6w), thedefinition of R⁷ is assumed by R^(7a), R^(7b), R^(7c), R^(7d), R^(7e),R^(7f), R^(7g), R^(7h), R^(7i), R^(7j), R^(7k), R^(7l), R^(7m), R^(7n),R^(7o), R^(7p), R^(7q), R^(7r), R^(7s), R^(7t), R^(7u), R^(7v), R^(7w),the definition of R⁸ is assumed by R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g), R^(8h), R^(8i), R^(8j), R^(8k), R^(8l), R^(8m),R^(8n), R^(8o), R^(8p), R^(8q), R^(8r), R^(8s), R^(8t), R^(8u), R^(8v),R^(8w), the definition of R⁹ is assumed by R^(9a), R^(9b), R^(9c),R^(9d), R^(9e), R^(9f), R^(9g), R^(9h), R^(9i), R^(9j), R^(9k), R^(9l),R^(9m), R^(9n), R^(9o), R^(9p), R^(9q), R^(9r), R^(9s), R^(9t), R^(9u),R^(9v), R^(9w), the definition of R¹⁰ is assumed by R^(10a), R^(10b),R^(10c), R^(10d), R^(10e), R^(10f), R^(10g), R^(10h), R^(10i), R^(10j),R^(10k), R^(10l), R^(10m), R^(10n), R^(10o), R^(10p), R^(10q), R^(10r),R^(10s), R^(10t), R^(10u), R^(10v), R^(10w), the definition of R¹¹ isassumed by R^(11a), R^(11b), R^(11c), R^(11d), R^(11e), R^(11f),R^(11g), R^(11h), R^(11i), R^(11j), R^(11k), R^(11l), R^(11m), R^(11n),R^(11o), R^(11p), R^(11q), R^(11r), R^(11s), R^(11t), R^(11u), R^(11v),R^(11w), the definition of R¹² is assumed by R^(12a), R^(12b), R^(12c),R^(12d), R^(12e), R^(12f), R^(12g), R^(12h), R^(12i), R^(12j), R^(12k),R^(12l), R^(12m), R^(12n), R^(12o), R^(12p), R^(12q), R^(12r), R^(12s),R^(12t), R^(12u), R^(12v), R^(12w), and/or R^(12w).

The variables used within a definition of R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², and/or other variables that appear at multipleinstances and are different may similarly be appropriately labeled todistinguish each group for greater clarity. In embodiments, theTLR-binding nucleic acid substituent is a TLR-binding nucleic acidsubstituent described herein, including in an aspect, embodiment,example, table, figure, or claim. In embodiments, the TLR-binding DNAsubstituent is a TLR-binding DNA substituent described herein, includingin an aspect, embodiment, example, table, figure, or claim. Inembodiments, the STAT-binding nucleic acid substituent is a STAT-bindingnucleic acid substituent described herein, including in an aspect,embodiment, example, table, figure, or claim. In embodiments, theSTAT3-binding nucleic acid substituent is a STAT3-binding nucleic acidsubstituent described herein, including in an aspect, embodiment,example, table, figure, or claim. In embodiments, the STAT-binding DNAsubstituent is a STAT-binding DNA substituent described herein,including in an aspect, embodiment, example, table, figure, or claim. Inembodiments, the STAT3-binding DNA substituent is a STAT3-binding DNAsubstituent described herein, including in an aspect, embodiment,example, table, figure, or claim. In embodiments, the Linker is a Linkerdescribed herein, including in an aspect, embodiment, example, table,figure, or claim. In embodiments, the Spacer is a Spacer describedherein, including in an aspect, embodiment, example, table, figure, orclaim. In embodiments, the Terminal moiety is a Terminal moietydescribed herein, including in an aspect, embodiment, example, table,figure, or claim. In embodiments, the compound is a compound describedherein, including in an aspect, embodiment, example, table, figure, orclaim.

Pharmaceutical Compositions

In an aspect is provided a pharmaceutical composition including apharmaceutically acceptable excipient and a compound, orpharmaceutically acceptable salt thereof, described herein (including inan aspect, embodiment, table, figure, claim, sequence listing, orexample). In embodiments of the pharmaceutical compositions, thecompound, or pharmaceutically acceptable salt thereof, as describedherein (including in an aspect, embodiment, table, figure, claim,sequence listing, or example), is included in a therapeuticallyeffective amount.

In embodiments, the pharmaceutical composition further includes a secondagent (e.g. therapeutic agent). In embodiments, the second agent is ananti-cancer agent. In embodiments, the second agent is an anti-viralagent. In embodiments of the pharmaceutical compositions, thepharmaceutical composition includes a second agent (e.g. therapeuticagent) in a therapeutically effective amount. In embodiments, thepharmaceutical composition is a vaccine formulation including a compounddescribed herein, a vaccine excipient, and an antigenic component. Inembodiments, the antigenic component is a cancer antigenic component. Inembodiments, the antigenic component is a tumor-associated antigen. Inembodiments, the pharmaceutical composition is a vaccine including acompound described herein, a vaccine excipient, and an antigeniccomponent.

Methods

In an aspect is provided a method of treating cancer in a patient inneed of the treatment, the method including administering a compound, orpharmaceutically acceptable salt thereof, described herein (including inan aspect, embodiment, table, figure, claim, sequence listing, orexample).

In an aspect is provided a method of treating a viral disease (e.g.herpesvirus infection associated disease or hepatitis virus infectionassociated disease or HIV infection associated disease) associated withSTAT3-dependent immunosuppression in a patient in need of the treatment,the method including administering a compound, or pharmaceuticallyacceptable salt thereof, described herein (including in an aspect,embodiment, table, figure, claim, sequence listing, or example).

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for treatment of a disease (e.g., cancer,infectious disease, virus associated disease). The use includesadministering to the subject a compound described herein. The use mayinclude administering to the subject a therapeutically effective amountof a compound described herein.

In an aspect is provided a compound as described herein for use in thetreatment of a cancer in a subject in need of such treatment. The useincludes administering to the subject a compound described herein. Theuse may include administering to the subject a therapeutically effectiveamount of a compound described herein.

In an aspect is provided a compound as described herein for use in thetreatment of a viral disease associated with STAT3-dependentimmunosuppression in a subject in need of such treatment. The useincludes administering to the subject a compound described herein. Theuse may include administering to the subject a therapeutically effectiveamount of a compound described herein.

In embodiments, the method or use includes administering atherapeutically effective amount of a compound described herein(including in an aspect, embodiment, table, figure, claim, sequencelisting, or example).

In embodiments, the method or use includes systemic administration ofthe compound. In embodiments, the method or use includes parenteraladministration of the compound. In embodiments, the method or useincludes intravenous administration of the compound. In embodiments, themethod or use includes administration directly to a tumor. Inembodiments, the method or use includes local administration to the siteof infection or cancer.

In embodiments, the cancer is a hematopoietic cell cancer. Inembodiments, the cancer is not a hematopoietic cell cancer. Inembodiments, the cancer is prostate cancer, breast cancer, glioblastoma,ovarian cancer, lung cancer, head and neck cancer, esophageal cancer,skin cancer, melanoma, brain cancer, colorectal cancer, leukemia,lymphoma, or myeloma. In embodiments, the cancer is prostate cancer(e.g. castration-resistant). In embodiments, the cancer is breast cancer(e.g. triple negative). In embodiments, the cancer is glioblastoma. Inembodiments, the cancer is ovarian cancer. In embodiments, the cancer islung cancer. In embodiments, the cancer is head and neck cancer. Inembodiments, the cancer is esophageal cancer. In embodiments, the canceris skin cancer. In embodiments, the cancer is melanoma. In embodiments,the cancer is brain cancer. In embodiments, the cancer is colorectalcancer. In embodiments, the cancer is leukemia (e.g. AML, ALL, or CML).In embodiments, the cancer is lymphoma. In embodiments, the cancer ismyeloma (e.g. multiple myeloma). In embodiments, the cancer is squamouscell carcinoma (e.g. head and neck cancer or esophageal cancer). Inembodiments, the cancer is metastatic cancer. In embodiments, the canceris acute myeloid leukemia. In embodiments, the cancer is B celllymphoma. In embodiments, the cancer is multiple myeloma. Inembodiments, the cancer is prostate cancer. In embodiments, the canceris glioblastoma. In embodiments, the cancer has an increased level ofSTAT3 (e.g. activity, mRNA, or protein) relative to a control (e.g.non-cancerous cell of the same type as the cancer cell). In embodiments,the cancer has an increased level of TLR9 relative to a control (e.g.non-cancerous cell of the same type as the cancer cell). In embodiments,the cancer has an increased level of TLR (e.g. endosomal TLR, TLR3,TLR7, TLR8, or TLR9) relative to a control (e.g. non-cancerous cell ofthe same type as the cancer cell). In embodiments, the cancer has anincreased level of phosphorylated STAT3 relative to a control (e.g.non-cancerous cell of the same type as the cancer cell). In embodiments,the cancer has an increased level of a STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) (e.g. activity,mRNA, or protein) relative to a control (e.g. non-cancerous cell of thesame type as the cancer cell). In embodiments, the cancer has anincreased level of phosphorylated STAT (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) relative to a control (e.g. non-cancerous cellof the same type as the cancer cell). In embodiments, the STAT is STAT1.In embodiments, the STAT is STAT2. In embodiments, the STAT is STAT3. Inembodiments, the STAT is STAT4. In embodiments, the STAT is STAT5A. Inembodiments, the STAT is STAT5B. In embodiments, the STAT is STAT6. Inembodiments, the STAT is human.

In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is HHV-1 infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is HHV-2 infection. Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is HHV-3 infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is HHV-4 infection. Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is HHV-5 infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is HHV-6A infection.In embodiments, the viral disease associated with STAT3-dependentimmunosuppression is HHV-6B infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is HHV-7 infection. Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is HHV-8 infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is hepatitis A virusinfection. In embodiments, the viral disease associated withSTAT3-dependent immunosuppression is hepatitis B virus infection. Inembodiments, the viral disease associated with STAT3-dependentimmunosuppression is hepatitis C virus infection. In embodiments, theviral disease associated with STAT3-dependent immunosuppression ishepatitis D virus infection. In embodiments, the viral diseaseassociated with STAT3-dependent immunosuppression is hepatitis E virusinfection. In embodiments, the viral disease associated withSTAT3-dependent immunosuppression is HIV infection.

In an aspect is provided a method of inhibiting the growth of a cancercell including contacting the cancer cell with a compound describedherein (including in an aspect, embodiment, table, figure, claim,sequence listing, or example).

In an aspect is provided a compound as described herein for use ininhibiting the growth of a cancer cell. The use includes contacting thecancer cell with a compound described herein. The use may includecontacting the cancer cell with an effective amount of a compounddescribed herein.

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for inhibiting the growth of a cancer cell.

In embodiments, the cancer cell includes a level of TLR (e.g. endosomalTLR, TLR3, TLR7, TLR8, or TLR9) greater than a non-cancerous cellcontrol. In embodiments, the cancer cell includes a level of TLR9greater than a non-cancerous cell control. In embodiments, the cancercell includes a level of a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) greater than a non-cancerouscell control. In embodiments, the STAT is STAT1. In embodiments, theSTAT is STAT2. In embodiments, the STAT is STAT3. In embodiments, theSTAT is STAT4. In embodiments, the STAT is STAT5A. In embodiments, theSTAT is STAT5B. In embodiments, the STAT is STAT6. In embodiments, theTLR is an endosomal TLR. In embodiments, the TLR is TLR3. Inembodiments, the TLR is TLR7. In embodiments, the TLR is TLR8. Inembodiments, the TLR is TLR9. In embodiments, the cancer cell includes alevel of STAT3 greater than a non-cancerous cell control. Inembodiments, the method or use includes inducing apoptosis of the cancercell. In embodiments, the method or use includes inducing apoptosis in acancer cell but not a non-cancer cell. In embodiments, the method or useincludes inducing apoptosis in a cancer cell in a patient but not anon-cancer cell in the same patient. In embodiments, the method or useincludes inducing apoptosis in a cancer cell but not a non-cancer cellof the same cell type as the cancer cell (e.g. lung cell, breast cell,pancreatic cell, colorectal cell, prostate cell, hematopoietic cell). Inembodiments, the cancer cell is in the brain. In embodiments, the cancercell is in an organ. In embodiments, the cancer cell is in a bone. Inembodiments, the cancer cell is in bone marrow.

In an aspect is provided a method of stimulating the immune system of apatient in need thereof including administering an effective amount of acompound, or pharmaceutically acceptable salt thereof, described herein(including in an aspect, embodiment, table, figure, claim, sequencelisting, or example).

In an aspect is provided a compound as described herein for use in themanufacture of a medicament for stimulating the immune system of apatient in need thereof.

In an aspect is provided a compound as described herein for use instimulating the immune system of a patient in need thereof. The useincludes administering to the subject a compound described herein. Theuse may include administering to the subject a therapeutically effectiveamount of a compound described herein.

In embodiments, the stimulating includes maturation, differentiation, orproliferation of natural killer cells, T cells, monocytes, ormacrophages. In embodiments, the stimulating includes an increase in aT_(H)1-type immune response. In embodiments, the stimulating includesincreases in T_(H)1-type immune responses. In embodiments, the method oruse includes contacting a plasmacytoid dendritic cell, myeloid dendriticcell, myeloid-derived suppressor cell, granulocytic myeloid-derivedsuppressor cell, macrophage, B cell, activated NK cell, or activatedneutrophil. In embodiments, the method or use includes stimulating aplasmacytoid dendritic cell, myeloid dendritic cell, myeloid-derivedsuppressor cell, granulocytic myeloid-derived suppressor cell,macrophage, B cell, activated NK cell, or activated neutrophil.

In an aspect is provided a method of reducing the activity of STAT3 in acell including contacting the cell with a compound described herein(including in an aspect, embodiment, table, figure, claim, sequencelisting, or example). In embodiments, the activity of STAT3 istranscriptional activity (e.g. transcriptional activation, increasingtranscription of a gene, or decreasing the transcription of a gene). Inembodiments, the activity of STAT3 is binding to a genomic DNA (e.g. ata STAT3 recognition site or STAT3 binding site).

In an aspect is provided a method of reducing the activity of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) in a cell including contacting the cell with a compounddescribed herein (including in an aspect, embodiment, table, figure,claim, sequence listing, or example). In embodiments, the activity of aSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) is transcriptional activity (e.g. transcriptionalactivation, increasing transcription of a gene, or decreasing thetranscription of a gene). In embodiments, the activity of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) is binding to a genomic DNA (e.g. at a STAT (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) recognition site or STAT(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) bindingsite). In embodiments, the STAT is STAT1. In embodiments, the STAT isSTAT2. In embodiments, the STAT is STAT3. In embodiments, the STAT isSTAT4. In embodiments, the STAT is STAT5A. In embodiments, the STAT isSTAT5B. In embodiments, the STAT is STAT6. In embodiments, the method oruse includes contacting a plasmacytoid dendritic cell, myeloid dendriticcell, myeloid-derived suppressor cell, granulocytic myeloid-derivedsuppressor cell, macrophage, B cell, activated NK cell, or activatedneutrophil. In embodiments, the method or use includes reducing theactivity of a STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) in a plasmacytoid dendritic cell,myeloid dendritic cell, myeloid-derived suppressor cell, granulocyticmyeloid-derived suppressor cell, macrophage, B cell, activated NK cell,or activated neutrophil.

In an aspect is provided a compound as described herein for use inreducing the activity of a STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) in a cell. The use includescontacting the cell with a compound described herein. The use mayinclude contacting the cell with an effective amount of a compounddescribed herein.

In embodiments, the method or use includes allowing the compound to bindthe STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6). In embodiments, the method or use includes allowingthe compound to bind the phosphorylated STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments,the method or use includes allowing the compound to bind thephosphorylated STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) in the cytosol. In embodiments, themethod or use includes allowing the compound to bind the phosphorylatedSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) and preventing the STAT transcription factor fromentering the nucleus. In embodiments, the method or use includesallowing the compound to bind the phosphorylated STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) andpreventing the STAT transcription factor from becoming dephosphorylated.In embodiments, the method or use includes allowing the compound to bindthe phosphorylated STAT transcription factor (e.g. STAT1, STAT2, STAT3,STAT4, STAT5A, STAT5B, or STAT6) and prevent binding of the STATtranscription factor to genomic DNA. In embodiments, the method or useincludes reducing the levels of a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments, themethod or use includes reducing the levels of activity of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6). In embodiments, the method or use includes reducing thelevels of transcription of a STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6). In embodiments, themethod or use includes reducing the levels of translation of a STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6). In embodiments, the method or use includes reducing thelevels of phosphorylated STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6).

In embodiments, the method or use includes contacting a cancer cell witha compound described herein. In embodiments, the method or use includesreducing the level of STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a disease associatedcell. In embodiments, the method or use includes reducing the level ofSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) activity in a cancer cell (e.g., leukemia cell,lymphoma cell, myeloma cell, solid tumor cell, acute myeloid leukemia(AML) cell, B cell lymphoma cell, multiple myeloma cell, prostate cancercell, or glioblastoma cell). In embodiments, the method or use includesreducing the level of STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a leukemia cell. Inembodiments, the method or use includes reducing the level of STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) activity in a cancer stem cell. In embodiments, the method oruse includes reducing the level of STAT transcription factor (e.g.STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a stemcell. In embodiments, the method or use includes reducing the level ofSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) activity in a solid tumor cell. In embodiments, themethod or use includes reducing the level of STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity ina prostate cancer cell. In embodiments, the method or use includesreducing the level of STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a cell. Inembodiments, the method or use includes reducing the level of STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) activity in an immune cell. In embodiments, the method or useincludes reducing the level of STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a leukocyte.In embodiments, the method or use includes reducing the level of STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) activity in a lymphocyte. In embodiments, the method or useincludes reducing the level of STAT transcription factor (e.g. STAT1,STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a dendriticcell. In embodiments, the method or use includes reducing the level ofSTAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6) activity in a plasmacytoid dendritic cell. Inembodiments, the method or use includes reducing the level of STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) activity in a myeloid dendritic cell. In embodiments, themethod or use includes reducing the level of STAT transcription factor(e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity ina macrophage cell. In embodiments, the method or use includes reducingthe level of STAT transcription factor (e.g. STAT1, STAT2, STAT3, STAT4,STAT5A, STAT5B, or STAT6) activity in a suppressor cell. In embodiments,the method or use includes reducing the level of STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)activity in a myeloid-derived suppressor cell (MDSC). In embodiments,the method or use includes reducing the level of STAT transcriptionfactor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, or STAT6)activity in a B cell. In embodiments, the method or use includesreducing the level of STAT transcription factor (e.g. STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6) activity in a T cell. Inembodiments, the method or use includes reducing the level of STATtranscription factor (e.g. STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B,or STAT6) activity in a granulocytic myeloid-derived suppressor cells(gMDSC). In embodiments, the method or use includes reducing the levelsuppression of the immune system. In embodiments, the method or useincludes increasing the level of TLR9 in a disease associated cell. Inembodiments, the method or use includes increasing the level of TLR9activity in a disease associated cell. In embodiments, the method or useincludes increasing the level of TLR9 activity in an immune cell. Inembodiments, the method or use includes increasing the level of TLR9activity in a cancer cell (e.g., leukemia cell, lymphoma cell, myelomacell, solid tumor cell, acute myeloid leukemia (AML) cell, B celllymphoma cell, multiple myeloma cell, prostate cancer cell, orglioblastoma cell).

In embodiments, the method or use includes increasing the level of CD8+cells. In embodiments, the method or use includes increasing the levelof immune effector cells. In embodiments, the method or use includesincreasing the level of T cells. In embodiments, the method or useincludes increasing the level of effector T cells. In embodiments, themethod or use includes decreasing the level of CD4+ cells. Inembodiments, the method or use includes decreasing the level ofCD4+/Fox3P+ cells. In embodiments, the method or use includes decreasingthe level of regulatory cells. In embodiments, the method or useincludes decreasing the level of regulatory T cells. In embodiments, themethod or use includes decreasing the level of suppressor cells. Inembodiments, the method or use includes decreasing the level ofsuppressor T cells. In embodiments, the method or use includesdecreasing the level of myeloid suppressor cells. In embodiments, themethod or use includes decreasing the level of immune systemsuppression. In embodiments, the method or use includes inducing theimmune system to recognize disease associated cells (e.g., cancer cells,infected cells). In embodiments, the method or use includes reducing thelevel of Arginase-1 in a cell (e.g., disease associated cell, cancercell, infected cell, immune cell). In embodiments, the method or useincludes increasing proliferation of T cells. In embodiments, the methodor use includes reducing the level of CD80 in a cell. In embodiments,the method or use includes reducing the level of CD86 in a cell. Inembodiments, the method or use includes reducing the level of CD48 in acell. In embodiments, the method or use includes reducing the level ofPDL-1. In embodiments, the method or use includes reducing the level ofT regulatory cells. In embodiments, the method or use includes reducingthe level of CD25+ cells. In embodiments, the method or use includesreducing the level of CTLA4+ cells. In embodiments, the method or useincludes increasing the level of CD28 in a cell. In embodiments, themethod or use includes reducing the level of CD15+ cells. Inembodiments, the method or use includes reducing the level of CD15 in acell. In embodiments, the method or use includes reducing the level ofCD15+ granulocytes.

In embodiments, the method or use includes systemic administration ofthe compound. In embodiments, the method or use includes parenteraladministration of the compound. In embodiments, the method or useincludes intravenous administration of the compound. In embodiments, themethod or use includes administration directly to a tumor. Inembodiments, the method or use includes local administration to the siteof infection or cancer.

Additional Embodiments

1. A compound comprising a TLR-binding nucleic acid substituentconjugated to a STAT-binding DNA substituent.

2. The compound of embodiment 1, wherein the STAT is human STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6.

3. The compound of embodiment 1, wherein the STAT is human STAT1, STAT2,STAT3, STAT4, STAT5A, STAT5B, or STAT6.

4. The compound of embodiment 1, wherein the STAT is human STAT1.

5. The compound of embodiment 1, wherein the STAT is human STAT2.

6. The compound of embodiment 1, wherein the STAT is human STAT3.

7. The compound of embodiment 1, wherein the STAT is human STAT4.

8. The compound of embodiment 1, wherein the STAT is human STAT5A.

9. The compound of embodiment 1, wherein the STAT is human STAT5B.

10. The compound of embodiment 1, wherein the STAT is human STAT6.

11. The compound of one of embodiments 1 to 10, wherein the TLR is anendosomal TLR.

12. The compound of one of embodiments 1 to 10, wherein the TLR is humanTLR3, TLR7, TLR8, or TLR9.

13. The compound of one of embodiments 1 to 10, wherein the TLR is humanTLR3.

14. The compound of one of embodiments 1 to 10, wherein the TLR is humanTLR7.

15. The compound of one of embodiments 1 to 10, wherein the TLR is humanTLR8.

16. The compound of one of embodiments 1 to 10, wherein the TLR is humanTLR9.

17. A compound comprising a TLR9-binding DNA substituent conjugated to aSTAT3-binding DNA substituent.

18. The compound of embodiment 17, wherein the TLR9-binding DNA subsubstituent comprises a CpG motif.

19. The compound of any one of embodiments 17 to 18, wherein theTLR9-binding DNA substituent comprises an unmethylated CpG motif.

20. The compound of any one of embodiments 17 to 19, wherein theTLR9-binding DNA substituent comprises a DNA sequence capable of forminga G-quadruplex.

21. The compound of any one of embodiments 17 to 20, wherein theTLR9-binding DNA substituent comprises a Class A CpG DNA sequence.

22. The compound of any one of embodiments 17 to 20, wherein theTLR9-binding DNA substituent comprises a Class B CpG DNA sequence.

23. The compound of any one of embodiments 17 to 20, wherein theTLR9-binding DNA substituent comprises a C-type CpG DNA sequence.

24. The compound of one of embodiments 17 to 23, wherein theSTAT3-binding DNA substituent comprises a first STAT3-binding DNAsequence covalently bound to a second STAT3-binding DNA sequence by aspacer; and the spacer is a substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

25. The compound of embodiment 24, wherein the spacer is a substitutedor unsubstituted C1-C40 alkylene, substituted or unsubstituted 2 to 40membered heteroalkylene, substituted or unsubstituted C3-C8cycloalkylene, substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted or unsubstituted C6-C10 arylene, orsubstituted or unsubstituted 5 to 10 membered heteroarylene.

26. The compound of embodiment 24, wherein the spacer is anunsubstituted C1-C40 alkylene, unsubstituted 2 to 40 memberedheteroalkylene, unsubstituted C3-C8 cycloalkylene, unsubstituted 3 to 8membered heterocycloalkylene, unsubstituted C6-C10 arylene, orunsubstituted 5 to 10 membered heteroarylene.

27. The compound of embodiment 24, wherein the spacer is a substituted 2to 40 membered heteroalkylene.

28. The compound of embodiment 24, wherein the spacer comprises one ormore substituted or unsubstituted alkyl phosphates.

29. The compound of embodiment 24, wherein the spacer is-L1-(PO4H-L2)n-, wherein L1 and L2 are independently a substituted orunsubstituted alkylene (e.g., n-propylene) and L1 is bonded to the firstSTAT3-binding DNA sequence by a 3′ phosphate moiety; n is an integerbetween 1 and 10 (e.g., 4); and the spacer is bonded to the second firstSTAT3-binding DNA sequence by a 5′ phosphate moiety.

30. The compound of one of embodiments 17 to 29, wherein theSTAT3-binding DNA substituent binds phosphorylated STAT3.

31. The compound of one of embodiments 17 to 29, wherein theSTAT3-binding DNA substituent binds to a STAT3 dimer.

32. The compound of one of embodiments 17 to 29, wherein theSTAT3-binding DNA substituent binds a phosphorylated STAT3 dimer.

33. The compound of one of embodiments 17 to 29, wherein theSTAT3-binding DNA substituent preferentially binds phosphorylated STAT3dimer over unphosphorylated STAT3 monomer.

34. The compound of one of embodiments 17 to 29, wherein theSTAT3-binding DNA substituent preferentially binds phosphorylated STAT3over unphosphorylated STAT3.

35. The compound of one of embodiments 24 to 34, wherein the firstSTAT3-binding DNA sequence comprises a first nucleic acid sequence andthe second STAT3-binding DNA sequence comprises a second nucleic acidsequence, wherein the first and second nucleic acid sequences arecomplementary.

36. The compound of one of embodiments 24 to 34, wherein the firstSTAT3-binding DNA sequence and second STAT3-binding DNA sequence form adouble-stranded STAT3-binding DNA sequence.

37. The compound of any one of embodiments 17 to 36, wherein theSTAT3-binding DNA substituent comprises a STAT3-binding DNA sequencecovalently bonded to a terminal moiety; and the terminal moiety is asubstituted or unsubstituted alkyl, substituted or unsubstitutedheteroalkyl, substituted or unsubstituted cycloalkyl, substituted orunsubstituted heterocycloalkyl, substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl.

38. The compound of embodiment 37, wherein the terminal moiety is asubstituted or unsubstituted C1-C40 alkyl, substituted or unsubstituted2 to 40 membered heteroalkyl, substituted or unsubstituted C3-C8cycloalkyl, substituted or unsubstituted 3 to 8 memberedheterocycloalkyl, substituted or unsubstituted C6-C10 aryl, orsubstituted or unsubstituted 5 to 10 membered heteroaryl.

39. The compound of embodiment 37, wherein the terminal moiety is asubstituted C1-C20 alkyl, substituted 2 to 20 membered heteroalkyl,substituted C3-C8 cycloalkyl, substituted 3 to 8 memberedheterocycloalkyl, substituted C6-C10 aryl, or substituted 5 to 10membered heteroaryl.

40. The compound of embodiment 37, wherein the terminal moiety is anunsubstituted C1-C40 alkyl, unsubstituted 2 to 40 membered heteroalkyl,unsubstituted C3-C8 cycloalkyl, unsubstituted 3 to 8 memberedheterocycloalkyl, unsubstituted C6-C10 aryl, or unsubstituted 5 to 10membered heteroaryl.

41. The compound of embodiment 37, wherein the terminal moiety is asubstituted 2 to 40 membered heteroalkyl.

42. The compound of embodiment 37, wherein the terminal moiety comprisesone or more substituted or unsubstituted alkyl phosphates.

43. The compound of embodiment 37, wherein the terminal moiety is-L1b-(PO4H-L2b)n2-H, wherein L1b and L2b are independently a substitutedor unsubstituted alkylene (e.g., n-propylene) and L1b is bonded to theSTAT3-binding DNA sequence by a 3′ phosphate moiety; n is an integerbetween 1 and 10 (e.g., 3 or 4); and the terminal moiety is optionallybonded to a terminal phosphate moiety or a terminal phospho-alkyl aminomoiety (e.g., PO4H C6-NH2).

44. The compound of embodiment 37, wherein the terminal moiety is an R1substituted C1-C40 alkyl, R1 substituted 2 to 40 membered heteroalkyl,R1 substituted C3-C8 cycloalkyl, R1 substituted 3 to 8 memberedheterocycloalkyl, R1 substituted C6-C10 aryl, or R1 substituted 5 to 10membered heteroaryl; and R1 is a detectable moiety or a therapeuticmoiety.

45. The compound of embodiment 44, wherein the terminal moiety is an R1substituted 2 to 40 membered heteroalkyl.

46. The compound of one of embodiments 44 to 45, wherein R1 is anoxygen, oxo, amino, or detectable moiety.

47. The compound of embodiment 46, wherein the detectable moiety is afluorescent dye, electron-dense reagent, enzyme, biotin, digoxigenin,paramagnetic molecule, paramagnetic nanoparticle, contrast agent,magnetic resonance contrast agent, X-ray contrast agent, Gadolinium,radioisotope, radionuclide, fluorodeoxyglucose, gamma ray emittingradionuclide, positron-emitting radionuclide, biocolloid, microbubble,iodinated contrast agent, barium sulfate, thorium dioxide, gold, goldnanoparticle, gold nanoparticle aggregate, fluorophore, two-photonfluorophore, hapten, protein, or fluorescent moiety.

48. The compound of one of embodiments 17 to 47, further comprising alinker between the TLR9-binding DNA substituent and the STAT3-bindingDNA substituent.

49. The compound of embodiment 48, wherein the linker is a substitutedor unsubstituted alkylene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.

50. The compound of embodiment 48, wherein the linker is a substitutedor unsubstituted C1-C40 alkylene, substituted or unsubstituted 2 to 40membered heteroalkylene, substituted or unsubstituted C3-C8cycloalkylene, substituted or unsubstituted 3 to 8 memberedheterocycloalkylene, substituted or unsubstituted C6-C10 arylene, orsubstituted or unsubstituted 5 to 10 membered heteroarylene.

51. The compound of embodiment 48, wherein the linker is anunsubstituted C1-C40 alkylene, unsubstituted 2 to 40 memberedheteroalkylene, unsubstituted C3-C8 cycloalkylene, unsubstituted 3 to 8membered heterocycloalkylene, unsubstituted C6-C10 arylene, orunsubstituted 5 to 10 membered heteroarylene.

52. The compound of embodiment 48, wherein the linker is a substituted 2to 40 membered heteroalkylene.

53. The compound of embodiment 48 to 52, wherein the linker comprisesone or more substituted or unsubstituted alkyl phosphates.

54. The compound of embodiment 48, wherein the linker is-L1a-(PO4H-L2a)n1-, wherein L1a and L2a are independently a substitutedor unsubstituted alkylene (e.g., n-propylene) and L1 is bonded to theTLR9-binding DNA substituent by a 3′ phosphate moiety; n is an integerbetween 1 and 10 (e.g., 3 or 4); and the linker is bonded to theSTAT3-binding DNA substituent by a 5′ phosphate moiety.

55. The compound of any one of embodiments 1 to 54, further comprising aphosphodiester derivative linkage.

56. The compound of any one of embodiments 1 to 54, further comprising aphosphodiester derivative linkage selected from a phosphoramidatelinkage, phosphorodiamidate linkage, phosphorothioate linkage,phosphorodithioate linkage, phosphonocarboxylic acid linkage,phosphonocarboxylate linkage, phosphonoacetic acid linkage,phosphonoformic acid linkage, methyl phosphonate linkage, boronphosphonate linkage, and O-methylphosphoroamidite linkage.

57. The compound of any one of embodiments 1 to 54, further comprising aplurality of phosphodiester derivative linkages.

58. The compound of any one of embodiments 1 to 54, further comprising aplurality of phosphodiester derivative linkages selected from the groupconsisting of phosphoramidate linkages, phosphorodiamidate linkages,phosphorothioate linkages, phosphorodithioate linkages,phosphonocarboxylic acid linkages, phosphonocarboxylate linkages,phosphonoacetic acid linkages, phosphonoformic acid linkages, methylphosphonate linkages, boron phosphonate linkages, andO-methylphosphoroamidite linkages.

59. The compound of any one of embodiments 1 to 58, comprising aphosphodiester derivative linkage in the TLR9-binding DNA substituent.

60. The compound of any one of embodiments 1 to 58, comprising aphosphodiester derivative linkage in the TLR9-binding DNA substituent,wherein the phosphodiester derivative linkage is selected from aphosphoramidate linkage, phosphorodiamidate linkage, phosphorothioatelinkage, phosphorodithioate linkage, phosphonocarboxylic acid linkage,phosphonocarboxylate linkage, phosphonoacetic acid linkage,phosphonoformic acid linkage, methyl phosphonate linkage, boronphosphonate linkage, and O-methylphosphoroamidite linkage.

61. The compound of any one of embodiments 1 to 60, comprising aphosphodiester derivative linkage in the STAT3-binding DNA substituent.

62. The compound of any one of embodiments 1 to 60, comprising aphosphodiester derivative linkage in the STAT3-binding DNA substituent,wherein the phosphodiester derivative linkage is selected from aphosphoramidate linkage, phosphorodiamidate linkage, phosphorothioatelinkage, phosphorodithioate linkage, phosphonocarboxylic acid linkage,phosphonocarboxylate linkage, phosphonoacetic acid linkage,phosphonoformic acid linkage, methyl phosphonate linkage, boronphosphonate linkage, and O-methylphosphoroamidite linkage

63. The compound of any one of embodiments 1 to 54, further comprising aphosphorothioate linkage.

64. The compound of any one of embodiments 1 to 54, further comprising aplurality of phosphorothioate linkages.

65. The compound of any one of embodiments 17 to 64, comprising aphosphorothioate linkage in the TLR9-binding DNA substituent.

66. The compound of any one of embodiments 17 to 65, comprising aphosphorothioate linkage in the STAT3-binding DNA substituent.

67. The compound of any one of embodiments 1 to 66, wherein thenucleotide sugars are deoxyribose.

68. A pharmaceutical composition comprising a pharmaceuticallyacceptable excipient and the compound of one of embodiments 1 to 67.

69. The pharmaceutical composition of embodiment 68, further comprisinga second therapeutic agent.

70. The pharmaceutical composition of embodiment 69, wherein the secondtherapeutic agent is an anti-cancer agent.

71. A method of treating cancer in a patient in need of such treatment,the method comprising administering a therapeutically effective amountof a compound of one of embodiments 1 to 67.

72. The method of embodiment 71, wherein the cancer is a hematopoieticcell cancer.

73. The method of embodiment 71, wherein the cancer is not ahematopoietic cell cancer.

74. The method of embodiment 71, wherein the cancer is leukemia.

75. The method of embodiment 71, wherein the cancer is acute myeloidleukemia.

76. The method of embodiment 71, wherein the cancer is a solid cancer.

77. The method of embodiment 71, wherein the cancer is a carcinoma.

78. The method of embodiment 71, wherein the cancer is prostate cancer.

79. The method of embodiment 71, wherein the cancer is prostate cancer,breast cancer, glioblastoma, ovarian cancer, lung cancer, head and neckcancer, esophageal cancer, skin cancer, melanoma, brain cancer,colorectal cancer, leukemia, lymphoma, or myeloma.

80. A method of treating an infectious disease in a patient in need ofsuch treatment, the method comprising administering a therapeuticallyeffective amount of a compound of one of embodiments 1 to 67.

81. The method of embodiment 80, wherein the infectious disease is viraldisease.

82. The method of embodiment 80, wherein the infectious disease aherpesvirus associated disease.

83. The method of embodiment 80, wherein the infectious disease aherpesvirus associated disease, wherein the herpesvirus is HHV-1, HHV-2,HHV-3, HHV-4, HHV-5, HHV-6A, HHV-6B, HHV-7, or HHV-8.

84. The method of embodiment 80, wherein the infectious disease is anHIV associated disease.

85. The method of embodiment 80, wherein the infectious disease is HIVinfection.

86. The method of embodiment 80, wherein the infectious disease is ahepatitis virus associated disease.

87. The method of embodiment 80, wherein the infectious disease is ahepatitis virus associated disease, wherein the hepatitis virus ishepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis Dvirus, or hepatitis E virus.

88. A method of inhibiting the growth of a cancer cell comprisingcontacting the cancer cell with a composition of one of embodiments 1 to67.

89. The method of embodiment 88, wherein the cancer cell comprises alevel of TLR9 greater than a non-cancerous cell control.

90. The method of embodiment 88, wherein the cancer cell comprises alevel of STAT3 greater than a non-cancerous cell control.

91. A method of stimulating the immune system of a patient in needthereof comprising administering an effective amount of a composition ofone of embodiments 1 to 67 to the patient.

92. The method of embodiment 91, wherein the stimulating comprisesmaturation, differentiation, or proliferation of natural killer cells, Tcells, monocytes, or macrophages.

93. The method of embodiment 91, wherein the stimulating comprises anincrease in TH1-type immune responses.

94. The method of embodiment 91, wherein the stimulating comprises anincrease in CD8+ cells.

95. The method of embodiment 91, wherein the stimulating comprises adecrease in regulatory cells.

96. The method of embodiment 91, wherein the stimulating comprises adecrease in suppressor cells.

97. The method of embodiment 91, wherein the stimulating comprises adecrease in myeloid suppressor cells.

98. The method of embodiment 91, wherein the stimulating comprises anincrease in CD8+ cells.

99. The method of embodiment 91, wherein the stimulating comprises adecrease in CD4+/FoxP3+ cells.

100. A method of stimulating the immune system of a patient in needthereof to recognize disease associated cells, comprising administeringan effective amount of a composition of one of embodiments 1 to 67 tothe patient.

101. A method of stimulating the immune system of a patient in needthereof to recognize disease associated cells, comprising administeringan effective amount of a composition of one of embodiments 1 to 67 tothe patient, wherein the disease associated cell is a cancer cell,cancer stem cell, or infected cell.

102. A method of reducing the activity of a STAT transcription factor ina cell comprising contacting the cell with a compound of one ofembodiments 1 to 67.

103. The method of embodiment 102, wherein the STAT transcription factoris STAT3.

104. A method of increasing apoptosis of a cell comprising contactingthe cell with a compound of one of embodiments 1 to 67.

105. A method of inducing apoptosis of a cell comprising contacting thecell with a compound of one of embodiments 1 to 67.

106. The method of one of embodiments 71 to 105, further comprisingcontacting a plasmacytoid dendritic cell, myeloid dendritic cell,myeloid-derived suppressor cell, granulocytic myeloid-derived suppressorcell, macrophage, T Cell, B cell, activated NK cell, or activatedneutrophil with the compound.

107. The method of one of embodiments 71 to 105, further comprisingcontacting a plasmacytoid with the compound.

108. The method of one of embodiments 71 to 105, further comprisingcontacting a dendritic cell with the compound.

109. The method of one of embodiments 71 to 105, further comprisingcontacting a myeloid dendritic cell with the compound.

110. The method of one of embodiments 71 to 105, further comprisingcontacting a myeloid-derived suppressor cell with the compound.

111. The method of one of embodiments 71 to 105, further comprisingcontacting a granulocytic myeloid-derived suppressor cell with thecompound.

112. The method of one of embodiments 71 to 105, further comprisingcontacting a macrophage with the compound.

113. The method of one of embodiments 71 to 105, further comprisingcontacting a T Cell with the compound.

114. The method of one of embodiments 71 to 105, further comprisingcontacting a B cell with the compound.

115. The method of one of embodiments 71 to 105, further comprisingcontacting an activated NK cell with the compound.

116. The method of one of embodiments 71 to 105, further comprisingcontacting an activated neutrophil with the compound.

117. The method of one of embodiments 71 to 116, further comprisingallowing the compound to contact a STAT transcription factor.

118. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact a STAT transcription factor, whereinthe STAT transcription factor is STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6.

119. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT1.

120. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT2.

121. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT3.

122. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT4.

123. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT5A.

124. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT5B.

125. The method of one of embodiments 71 to 117, further comprisingallowing the compound to contact STAT6.

126. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor.

127. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor.

128. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor in the cytosol of a cell.

129. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor in the cytosol of a cell.

130. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from entering thenucleus.

131. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from entering thenucleus.

132. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from becomingdephosphorylated.

133. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from becomingdephosphorylated.

134. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from binding genomicDNA.

135. The method of one of embodiments 71 to 125, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from bindinggenomic DNA.

136. The method of one of embodiments 71 to 135, further comprisingreducing the level of a STAT transcription factor in a cell.

137. The method of one of embodiments 71 to 135, further comprisingreducing the level of a STAT3 transcription factor in a cell.

138. The method of one of embodiments 71 to 135, further comprisingreducing the level of a phosphorylated STAT transcription factor in acell.

139. The method of one of embodiments 71 to 135, further comprisingreducing the level of a phosphorylated STAT3 transcription factor in acell.

140. The method of one of embodiments 71 to 135, further comprisingreducing the level of activity of a STAT transcription factor in a cell.

141. The method of one of embodiments 71 to 135, further comprisingreducing the level of activity of a STAT3 transcription factor in acell.

142. The method of one of embodiments 71 to 135, further comprisingincreasing the level of activity of TLR9 in a cell.

143. The method of one of embodiments 71 to 135, further comprisingincreasing the level of activity of TLR9 in a disease associated cell.

144. The method of one of embodiments 71 to 135, further comprisingincreasing the level of activity of TLR9 in a cancer cell.

145. The method of one of embodiments 71 to 135, further comprisingincreasing the level of activity of TLR9 in a cancer cell, wherein thecancer cell is a leukemia cell, lymphoma cell, myeloma cell, solid tumorcell, acute myeloid leukemia (AML) cell, B cell lymphoma cell, multiplemyeloma cell, prostate cancer cell, or glioblastoma cell.

146. The method of one of embodiments 71 to 145, further comprisingreducing the level of Arginase-1 in a cell.

147. The method of one of embodiments 71 to 145, further comprisingincreasing the proliferation of T cells.

148. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD80 in a cell.

149. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD86 in a cell.

150. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD48 in a cell.

151. The method of one of embodiments 71 to 145, further comprisingreducing the level of PDL-1 in a cell.

152. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD25+ cells.

153. The method of one of embodiments 71 to 145, further comprisingreducing the level of CTLA4+ cells.

154. The method of one of embodiments 71 to 145, further comprisingincreasing the level of CD28 in a cell.

155. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD15+ cells.

156. The method of one of embodiments 71 to 145, further comprisingreducing the level of CD15+ granulocytes.

157. The method of one of embodiments 71 to 156, comprising systemicadministration of the compound.

158. The method of one of embodiments 71 to 156, comprising parenteraladministration of the compound.

159. The method of one of embodiments 71 to 156, comprising intravenousadministration of the compound.

160. The method of one of embodiments 71 to 156, comprising localadministration of the compound to the disease associated cells.

161. A compound of one of embodiments 1 to 67 for use in the treatmentof a cancer in a subject in need of such treatment, the use comprisingadministering a therapeutically effective amount of the compound.

162. The use of embodiment 161, wherein the cancer is a hematopoieticcell cancer.

163. The use of embodiment 161, wherein the cancer is not ahematopoietic cell cancer.

164. The use of embodiment 161, wherein the cancer is leukemia.

165. The use of embodiment 161, wherein the cancer is acute myeloidleukemia.

166. The use of embodiment 161, wherein the cancer is a solid cancer.

167. The use of embodiment 161, wherein the cancer is a carcinoma.

168. The use of embodiment 161, wherein the cancer is prostate cancer.

169. The use of embodiment 161, wherein the cancer is prostate cancer,breast cancer, glioblastoma, ovarian cancer, lung cancer, head and neckcancer, esophageal cancer, skin cancer, melanoma, brain cancer,colorectal cancer, leukemia, lymphoma, or myeloma.

170. A compound of one of embodiments 1 to 67 for use in the treatmentof an infectious disease in a subject in need of such treatment, the usecomprising administering a therapeutically effective amount of thecompound.

171. The use of embodiment 170, wherein the infectious disease is viraldisease.

172. The use of embodiment 170, wherein the infectious disease aherpesvirus associated disease.

173. The use of embodiment 170, wherein the infectious disease aherpesvirus associated disease, wherein the herpesvirus is HHV-1, HHV-2,HHV-3, HHV-4, HHV-5, HHV-6A, HHV-6B, HHV-7, or HHV-8.

174. The use of embodiment 170, wherein the infectious disease is an HIVassociated disease.

175. The use of embodiment 170, wherein the infectious disease is HIVinfection.

176. The use of embodiment 170, wherein the infectious disease is ahepatitis virus associated disease.

177. The use of embodiment 170, wherein the infectious disease is ahepatitis virus associated disease, wherein the hepatitis virus ishepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis Dvirus, or hepatitis E virus.

178. A compound of one of embodiments 1 to 67 for use in inhibiting thegrowth of a cancer cell comprising contacting the cancer cell with thecompound.

179. The use of embodiment 178, wherein the cancer cell comprises alevel of TLR9 greater than a non-cancerous cell control.

180. The use of embodiment 178, wherein the cancer cell comprises alevel of STAT3 greater than a non-cancerous cell control.

181. A compound of one of embodiments 1 to 67 for use in stimulating theimmune system of a patient in need thereof comprising administering aneffective amount of the compound to the patient.

182. The use of embodiment 181, wherein the stimulating comprisesmaturation, differentiation, or proliferation of natural killer cells, Tcells, monocytes, or macrophages.

183. The use of embodiment 181, wherein the stimulating comprises anincrease in TH1-type immune responses.

184. The use of embodiment 181, wherein the stimulating comprises anincrease in CD8+ cells.

185. The use of embodiment 181, wherein the stimulating comprises adecrease in regulatory cells.

186. The use of embodiment 181, wherein the stimulating comprises adecrease in suppressor cells.

187. The use of embodiment 181, wherein the stimulating comprises adecrease in myeloid suppressor cells.

188. The use of embodiment 181, wherein the stimulating comprises anincrease in CD8+ cells.

189. The use of embodiment 181, wherein the stimulating comprises adecrease in CD4+/FoxP3+ cells.

190. A compound of one of embodiments 1 to 67 for use in stimulating theimmune system of a patient in need thereof to recognize diseaseassociated cells, comprising administering an effective amount of thecomposition to the patient.

191. A compound of one of embodiments 1 to 67 for use in stimulating theimmune system of a patient in need thereof to recognize diseaseassociated cells, comprising administering an effective amount of thecompound to the patient, wherein the disease associated cell is a cancercell, cancer stem cell, or infected cell.

192. A compound of one of embodiments 1 to 67 for use in reducing theactivity of a STAT transcription factor in a cell comprising contactingthe cell with the compound.

193. The use of embodiment 192, wherein the STAT transcription factor isSTAT3.

194. A use of increasing apoptosis of a cell comprising contacting thecell with a compound of one of embodiments 1 to 67.

195. A use of inducing apoptosis of a cell comprising contacting thecell with a compound of one of embodiments 1 to 67.

196. The use of one of embodiments 161 to 195, further comprisingcontacting a plasmacytoid dendritic cell, myeloid dendritic cell,myeloid-derived suppressor cell, granulocytic myeloid-derived suppressorcell, macrophage, T Cell, B cell, activated NK cell, or activatedneutrophil with the compound.

197. The use of one of embodiments 161 to 195, further comprisingcontacting a plasmacytoid with the compound.

198. The use of one of embodiments 161 to 195, further comprisingcontacting a dendritic cell with the compound.

199. The use of one of embodiments 161 to 195, further comprisingcontacting a myeloid dendritic cell with the compound.

200. The use of one of embodiments 161 to 195, further comprisingcontacting a myeloid-derived suppressor cell with the compound.

201. The use of one of embodiments 161 to 195, further comprisingcontacting a granulocytic myeloid-derived suppressor cell with thecompound.

202. The use of one of embodiments 161 to 195, further comprisingcontacting a macrophage with the compound.

203. The use of one of embodiments 161 to 195, further comprisingcontacting a T Cell with the compound.

204. The use of one of embodiments 161 to 195, further comprisingcontacting a B cell with the compound.

205. The use of one of embodiments 161 to 195, further comprisingcontacting an activated NK cell with the compound.

206. The use of one of embodiments 161 to 195, further comprisingcontacting an activated neutrophil with the compound.

207. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a STAT transcription factor.

208. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a STAT transcription factor, whereinthe STAT transcription factor is STAT1, STAT2, STAT3, STAT4, STAT5A,STAT5B, or STAT6.

209. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT1.

210. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT2.

211. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT3.

212. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT4.

213. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT5A.

214. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT5B.

215. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact STAT6.

216. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor.

217. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor.

218. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor in the cytosol of a cell.

219. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor in the cytosol of a cell.

220. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from entering thenucleus.

221. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from entering thenucleus.

222. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from becomingdephosphorylated.

223. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from becomingdephosphorylated.

224. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT transcriptionfactor and preventing the STAT transcription factor from binding genomicDNA.

225. The use of one of embodiments 161 to 206, further comprisingallowing the compound to contact a phosphorylated STAT3 transcriptionfactor and preventing the STAT3 transcription factor from bindinggenomic DNA.

226. The use of one of embodiments 161 to 225, further comprisingreducing the level of a STAT transcription factor in a cell.

227. The use of one of embodiments 161 to 225, further comprisingreducing the level of a STAT3 transcription factor in a cell.

228. The use of one of embodiments 161 to 225, further comprisingreducing the level of a phosphorylated STAT transcription factor in acell.

229. The use of one of embodiments 161 to 225, further comprisingreducing the level of a phosphorylated STAT3 transcription factor in acell.

230. The use of one of embodiments 161 to 225, further comprisingreducing the level of activity of a STAT transcription factor in a cell.

231. The use of one of embodiments 161 to 225, further comprisingreducing the level of activity of a STAT3 transcription factor in acell.

232. The use of one of embodiments 161 to 231, further comprisingincreasing the level of activity of TLR9 in a cell.

233. The use of one of embodiments 161 to 231, further comprisingincreasing the level of activity of TLR9 in a disease associated cell.

234. The use of one of embodiments 161 to 231, further comprisingincreasing the level of activity of TLR9 in a cancer cell.

235. The use of one of embodiments 161 to 231, further comprisingincreasing the level of activity of TLR9 in a cancer cell, wherein thecancer cell is a leukemia cell, lymphoma cell, myeloma cell, solid tumorcell, acute myeloid leukemia (AML) cell, B cell lymphoma cell, multiplemyeloma cell, prostate cancer cell, or glioblastoma cell.

236. The use of one of embodiments 161 to 235, further comprisingreducing the level of Arginase-1 in a cell.

237. The use of one of embodiments 161 to 235, further comprisingincreasing the proliferation of T cells.

238. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD80 in a cell.

239. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD86 in a cell.

240. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD48 in a cell.

241. The use of one of embodiments 161 to 235, further comprisingreducing the level of PDL-1 in a cell.

242. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD25+ cells.

243. The use of one of embodiments 161 to 235, further comprisingreducing the level of CTLA4+ cells.

244. The use of one of embodiments 161 to 235, further comprisingincreasing the level of CD28 in a cell.

245. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD15+ cells.

246. The use of one of embodiments 161 to 235, further comprisingreducing the level of CD15+ granulocytes.

247. The use of one of embodiments 161 to 246, comprising systemicadministration of the compound.

248. The use of one of embodiments 161 to 246, comprising parenteraladministration of the compound.

249. The use of one of embodiments 161 to 246, comprising intravenousadministration of the compound.

250. The use of one of embodiments 161 to 246, comprising localadministration of the compound to the disease associated cells.

251. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for treatment of a cancer in a subject in need of suchtreatment, the use comprising administering a therapeutically effectiveamount of the compound.

252. The use of embodiment 251, wherein the cancer is a hematopoieticcell cancer.

253. The use of embodiment 251, wherein the cancer is not ahematopoietic cell cancer.

254. The use of embodiment 251, wherein the cancer is leukemia.

255. The use of embodiment 251, wherein the cancer is acute myeloidleukemia.

256. The use of embodiment 251, wherein the cancer is a solid cancer.

257. The use of embodiment 251, wherein the cancer is a carcinoma.

258. The use of embodiment 251, wherein the cancer is prostate cancer.

259. The use of embodiment 251, wherein the cancer is prostate cancer,breast cancer, glioblastoma, ovarian cancer, lung cancer, head and neckcancer, esophageal cancer, skin cancer, melanoma, brain cancer,colorectal cancer, leukemia, lymphoma, or myeloma.

260. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for treatment of an infectious disease in a subject inneed of such treatment, the use comprising administering atherapeutically effective amount of the compound.

261. The use of embodiment 260, wherein the infectious disease is viraldisease.

262. The use of embodiment 260, wherein the infectious disease aherpesvirus associated disease.

263. The use of embodiment 260, wherein the infectious disease aherpesvirus associated disease, wherein the herpesvirus is HHV-1, HHV-2,HHV-3, HHV-4, HHV-5, HHV-6A, HHV-6B, HHV-7, or HHV-8.

264. The use of embodiment 260, wherein the infectious disease is an HIVassociated disease.

265. The use of embodiment 260, wherein the infectious disease is HIVinfection.

266. The use of embodiment 260, wherein the infectious disease is ahepatitis virus associated disease.

267. The use of embodiment 260, wherein the infectious disease is ahepatitis virus associated disease, wherein the hepatitis virus ishepatitis A virus, hepatitis B virus, hepatitis C virus, hepatitis Dvirus, or hepatitis E virus.

268. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for inhibiting the growth of a cancer cell comprisingcontacting the cancer cell with the compound.

269. The use of embodiment 268, wherein the cancer cell comprises alevel of TLR9 greater than a non-cancerous cell control.

270. The use of embodiment 268, wherein the cancer cell comprises alevel of STAT3 greater than a non-cancerous cell control.

271. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for stimulating the immune system of a patient in needthereof comprising administering an effective amount of the compound tothe patient.

272. The use of embodiment 271, wherein the stimulating comprisesmaturation, differentiation, or proliferation of natural killer cells, Tcells, monocytes, or macrophages.

273. The use of embodiment 271, wherein the stimulating comprises anincrease in TH1-type immune responses.

274. The use of embodiment 271, wherein the stimulating comprises anincrease in CD8+ cells.

275. The use of embodiment 271, wherein the stimulating comprises adecrease in regulatory cells.

276. The use of embodiment 271, wherein the stimulating comprises adecrease in suppressor cells.

277. The use of embodiment 271, wherein the stimulating comprises adecrease in myeloid suppressor cells.

278. The use of embodiment 271, wherein the stimulating comprises anincrease in CD8+ cells.

279. The use of embodiment 271, wherein the stimulating comprises adecrease in CD4+/FoxP3+ cells.

280. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for stimulating the immune system of a patient in needthereof to recognize disease associated cells, comprising administeringan effective amount of the composition to the patient.

281. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for stimulating the immune system of a patient in needthereof to recognize disease associated cells, comprising administeringan effective amount of the compound to the patient, wherein the diseaseassociated cell is a cancer cell, cancer stem cell, or infected cell.

282. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for reducing the activity of a STAT transcription factorin a cell comprising contacting the cell with the compound.

283. The use of embodiment 282, wherein the STAT transcription factor isSTAT3.

284. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for increasing apoptosis of a cell comprising contactingthe cell with the compound.

285. Use of a compound of one of embodiments 1 to 67 in the manufactureof a medicament for inducing apoptosis of a cell comprising contactingthe cell with the compound.

EXAMPLES

A. Design of CpG-STAT3 Decoy Oligodeoxynucleotide (dODN) and ChemicalModification for Enhanced Serum Stability

Sequence of the single stranded CpG-STAT3 dODN conjugate (MW=17,757g/mol) (FIG. 1A). Asterisks indicate phosphothioation sites in theconjugate backbone; x=single unit of the C3 carbon chain (CH₂)₃ (GlenResearch) or combined x's equal an alkylphosphate (e.g. 5x is n=4 or 5xis n1=4, as n and n1 and n2 are used herein for alkylphosphates).Predicted hairpin structure of the folded CpG-STAT3 dODN with both partsof the conjugate indicated (FIG. 1B), wherein o=x (e.g. C3 carbon chainor alkylphosphate) as in FIG. 1A. Chemically-modified CpG-STAT3 dODN hasimproved resistance to degradation in human serum (FIG. 1C). Left twopanels of FIG. 1C—CpG-STAT3 dODN was incubated in 20% (right panel) or60% (middle panel) human serum for up to 168 h (1 week), then resolvedon 7.5M Urea/15% PAGE gel and stained using ethidium bromide. Bar graphshows quantification of band intensities in the middle panel. Theestimated half-life of CpG(A)-STAT3dODN in 60% human serum exceeds 2days. Right panel of FIG. 1C—incubation of the control CpG-dsRNA insimilar conditions results in conjugate cleavage already after 1 h.Shown are results from one of three independent experiments.

B. CpG-STAT3 dODN Conjugates but not Unconjugated STAT3 dODN are QuicklyInternalized by Various Target Human Cancer Cells In Vitro

Human acute myeloid leukemia, B cell lymphoma and prostate cancer cellswere incubated with two doses of fluorescently-labeled CpG-STAT3 dODN(left two columns of FIG. 2) or STAT3 dODN alone (right two columns ofFIG. 2) for indicated times without any transfection reagents.Percentages of Cy3-positive cells were assessed using flow cytometry(FIG. 2).

C. Targeted Delivery of CpG-STAT3 dODN into Mouse Immune Cells andCancer Cells In Vitro

Mouse splenocytes were incubated with fluorescently-labeled CpG-STAT3dODN in indicated concentrations for 2 h without any transfectionreagents (FIG. 3A). Percentages of Cy3-positive cells pDCs(CD11c+B220+), mDCs (CD11c+B220−), macrophages (MAC; F4/80+Gr1−), Bcells (B220+CD11c−), granulocytes (Gr1+F4/80−) and T cells (CD3+) wereassessed using flow cytometry (FIG. 3A). Rapid internalization ofCpG-STAT3 dODN by transformed mouse macrophages (RAW264.7) and varioustypes of mouse cancer cells, such as M2 and B16 melanoma, TC2neuroendocrine and MB49 bladder cancer cells (FIG. 3B). Cell wereincubated in the presence of 500 nM of CpG(B)-STAT3 dODN conjugate,which uses B-type CpG sequence optimized for immunostimulation in mice.CpG(A)-STAT3 dODN, with A-type CpG sequence optimized forimmunostimulation of human cells is internalized with similar efficiencyas CpG(B)-STAT3 dODN by mouse macrophages and cancer cells (FIG. 3C).

D. CpG-STAT3 dODN Colocalized with STAT3 Protein Shortly afterIntracellular Uptake into Early Endosomes

Mouse RAW264.7 macrophages were incubated with fluorescently-labeledCpG-STAT3 dODNCy3 at 500 nM concentration for 30 min (A) and 120 min (B)then fixed and permeabilized for immunostaining using antibodiesspecific to early endosome marker EEA1 (FIG. 4A) or to STAT3 (FIG. 4B)and counterstained using DAPi to visualize nuclei. The intracellularlocalization of CpG-STAT3 dODN was analyzed using confocal microscopy.Shown in FIGS. 4A-4B are representative images from one of twoindependent experiments.

E. CpG-STAT3 dODN Conjugates Inhibit DNA Binding of STAT3 in TargetHuman and Mouse Cancer Cells

Human DU145 prostate cancer cells and mouse M2 melanoma cells wereincubated in the presence of 500 nM of various CpG-dODN conjugates orunconjugated dODN (FIG. 5). Cells were then lysed to isolate nuclearextracts and the DNA binding of STAT3 was assessed using electromobilityshift assay (EMSA). The identity of the band representing STAT3homodimer was verified using antibodies specific to STAT3 as indicated(FIG. 5). Positions of inhibitory CpG-STAT3 dODNs are indicated in gray(CpG(A)-STAT3 dODN, CpG(B)-STAT3 dODN), (FIG. 5).

F. CpG-STAT3 dODN Induces Direct Cytotoxic Effects in Human and MouseCancer Cells In Vitro

Human B cell lymphoma (Daudi), AML (MV4-11) and prostate cancer cells(DU145) were incubated with 500 nM CpG(A)-STAT3 dODN for 2 days (FIG.6A). The induction of cell death was measured after Annexin V and 7AADstaining using flow cytometry. The percentages of early apoptotic(Annexin V+7AAD−) and late apoptotic (Annexin V+7AAD+) cells is shown.Mouse M2 melanoma and Cbfb/MYH11/Mp11 AML (CMM) cells were incubated 500nM CpG(B)-STAT3 dODN for 2 days and analyzed as described as above,(FIG. 6B).

G. Systemic CpG(A)-STAT3 dODN Treatment Induces Regression ofDisseminated Human MV4-11 Leukemia in Mice

NSG mice were injected i.v. with 0.5×10⁶ MV4-11luc acute myeloidleukemia cells (FIGS. 7A-7B). After 2-3 weeks when tumors were engraftedas confirmed by Xenogen imaging, mice were injected daily using 5 mg/kgof CpG(A)-STAT3 dODN or negative control CpG(A)-scrODN or leftuntreated. Xenogen imaging before and during treatment to detect AMLregression after repeated injections of CpG(A)-STAT3 dODN compared toboth control groups (FIG. 7A). CpG(A)-STAT3 dODN treatment reduces thepercentage of AML cells in various organs including bone marrow (BM) andblood as assessed using flow cytometry (FIG. 7B). Shown are combinedresults from 6 mice/group; means±SEM.

H. Systemic CpG-STAT3 dODN Treatment Induces Complete Regression ofMouse Cbfb/MYH11/Mpl Leukemia in Immunocompetent Mice

After 2-3 weeks when tumors were engrafted (>1%, ranging 1-5% of AMLcells in blood), mice were injected six times with CpG-Stat3 siRNA orcontrol CpG-Luciferase siRNA (5 mg/kg) every other day and euthanizedone day after last treatment (FIGS. 8A-8C). CpG-STAT3 dODN treatmentreduces the percentage of AML cells in various organs (FIGS. 8A-8C). Theeffect of CpG-STAT3 dODN treatments on spleen cellularity (FIG. 8A).Shown are representative spleen sizes (left) and the measurement ofspleens weight (right). Flow cytometric analysis of GFP+c-Kit⁺ AML cellsin blood, bone marrows, spleens and the percentage of CD8+ T cellsinfiltrating spleens from various groups of mice (FIGS. 8B-8C). Shownare combined results from 6 mice/group; means±SEM.

I. In Vivo Administration of CpG-STAT3dODN Reduces Leukemia-InitiatingPotential of Cbfb/MYH11/Mpl AML Cells

AML cells were enriched from spleens of primary recipient mice treatedusing CpG-STAT3dODN or CpG-scrambled ODN (5 mg/kg) injected i.v. 6 timesevery other day or untreated as described in FIGS. 8A-8C (FIG. 9).Leukemic cells from each treatment group were pooled, counted andinjected at identical cell numbers into secondary recipient mice. Micesurvival was monitored daily without any further treatment orintervention. Shown in FIG. 9 are results from a single experiment using10 mice per each group.

J. Intravenously Injected CpG-STAT3dODN Conjugates are More Effectivethan CpG-Stat3 siRNA Against Disseminated Leukemia In Vivo

After 2-3 weeks from tumor challenge, with confirmed AML engraftment(>1%, ranging 1-5% of AML cells in blood), mice were injected iv. only 3times every other day using 5 mg/kg of CpG(B)-Stat3 siRNA,CpG(A)-STAT3dODN, CpG(B)-STAT3dODN or CpG(B)-scrambled ODN conjugatesand euthanized one day after the last treatment (FIGS. 10A-10C).Treatments using both types of CpG-STAT3 dODN were more effective thanCpG-Stat3 siRNA in reducing percentages of AML cells in blood (FIG.10A), lymph nodes (FIG. 10B) and bone marrow (FIG. 10C). Shown arecombined results from 6 mice/group; means±SEM.

K. CpG-dODN Conjugates are Strongly Immunostimulatory Comparing to theUnconjugated Decoy STAT3

RAW-Blue cells with stable expression of the NF-κB-responsivepromoter/SEAP reporter gene construct were incubated in the presence of250 nM of indicated oligonucleotides or left untreated (FIG. 11). After24 hrs the SEAP activity was assessed colorimetrically in cell culturesupernatants. The results derived from triplicates were shown asmeans±SD (FIG. 11).

L. CpG(A)-STAT3dODN Induce Potent Immunostimulatory Effects in HumanImmune Cells Derived from Late-Stage Prostate Cancer Patients

PBMCs isolated from prostate cancer patients were incubated in 10%autologous patients' plasma in the presence of the indicatedoligonucleotides (125 nM each) (FIG. 12). After 36 h, cells were lysedand the expression of CXCL-10/IP-10 mRNA was assessed in total RNAsamples using real-time qPCR (Roche). Results were normalized to TBPgene expression and recalculated as fold induction using the level inuntreated PBMCs as a 1; ND—not detectable; means±SEM (n=3) (FIG. 12).

M. CpG-STAT3dODN but not the Unconjugated STAT3dODN is EfficientlyInternalized by Bone-Marrow Resident Leukemia Cells and Tumor-AssociatedMyeloid Cells

CMM+ AML-bearing C57BL/6 mice (n=6) were injected with a singleintravenous 5 mg/kg dose of Cy3-labeled CpGSTAT3dODN (FIG. 13 top row)or STAT3dODN alone (FIG. 13 bottom row). The biodistribution offluorescently labeled oligonucleotides was assessed in the indicatedorgans at 3 or 18 hrs after injection using flow cytometry. Theinternalization by bone marrow-resident leukemia cells was indicated byrectangles (FIG. 13). Results are representative of two independentexperiments.

N. CpG-STAT3dODN but not the Unconjugated STAT3dODN Targets PerivascularMacrophages in the Brain

Naïve C57BL/6 mice (n=4) were injected with a single intravenous 5 mg/kgdose of Cy3-labeled CpG(A)-STAT3dODN, CpG(B)-STAT3dODN or STAT3dODNalone as indicated (FIGS. 14A-14B). The uptake of fluorescently labeledoligonucleotides by total myeloid cells (FIG. 14A) and perivascularmacrophages (FIG. 14B) was assessed using flow cytometry in braintissues collected at 18 hrs after injection.

O. CpG(A)-STAT3dODN is not Cytotoxic for Normal Human Immune Cells

PBMCs isolated from healthy subjects were incubated in the presence ofvarious concentrations of CpG(A)-STAT3dODN or control CpG(A)-scrambledODN (FIGS. 15A-15C). Cells were collected after 72 h to analyzepercentages of Annexin V-positive apoptotic cells among CD3⁺ T cells(FIG. 15A), CD19⁺ B cells (FIG. 15B) and CD303⁺ pDC (FIG. 15C) usingflow cytometry. Shown are means±SEM (n=3)

P. Experimental Materials and Methods

Cells and Mice.

Cbfb^(+/56M)/Mx-Cre⁺ mice (Kuo et al. Cancer Cell 2006) were backcrossedto wild-type C57BL/6 mice for >10 generations to generate the syngeneicAML model. Two weeks after poly(I:C)-induced (Invivogen) expression ofCBFβ-SMMHC, bone marrow cells from Cbfb^(+/56M)/MX-Cre⁺ mice weretransduced with retroviral MIG-Mpl vector encoding thrombopoietinreceptor and GFP genes to generate transplantable Cbfb-MYH11/Mpt⁺ mouseAML (Landrette et al. Leukemia. 2011). Mouse RAW264.7 macrophages andhuman PC3, DU145 prostate cancer cells were purchased from ATCC. Thereporter RAW-Blue cells were obtained from Imgenex and handled assuggested by the manufacturer. Human KG1a, MV4-11 leukemia and Raji,REC1 lymphoma cell lines were obtained. Mousec B16-F10 melanoma,TRAMP-C2 (TC2) prostate cancer, MB49 bladder cancer and K1739-M2melanoma cells were kindly provided. Healthy PBMCs were isolated fromdiscarded blood samples from anonymous donors provided by the BloodDonor Center at City of Hope.

Reagents.

The CpG-siRNAs were synthesized in the DNA/RNA Synthesis Core (COH) bylinking CpG(B)-ODN (CpG1668), CpG(A) (D19) or GpC(A) to STAT3 decoy orscrambled ODN sequences similarly as previously described (Kortylewskiet al. Nat. Biotech. 2009) using 4-5 units of C3 carbon chain, (CH₂)₃(Glen Research, VA). The resulting ODN conjugates are shown below, xindicates a single C3 unit bonded to phosphate groups at both ends,except at the 5′ end and 3′ end where the last 3′ x is —C⁶—NH₂ followingthe final phosphate group and a 5′ terminal x has an OH group at theterminus. A 5′ nucleotide has a terminal 5′ OH group. Asterisks indicatephosphothioation sites):

CpG(A)-STAT3dODN (SEQ ID NO: 6) 5′G*G*TGCATCGATGCAGG*G*G*G*G-xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx 3′ GpC(A)-STAT3dODN (SEQ ID NO: 7)5′ G*G*TGCATGCATGCAGG*G*G*G*G-xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx 3′ CpG(A)-scrambled ODN(SEQ ID NO: 8) 5′ G*G*TGCATCGATGCAGG*G*G*G*G-xxxxx- A*C*T*CTTGCCAATTAC-xxxx-GTAATTGGCAAG*A*G*T-xxxxx 3′ CpG(B)-STAT3 dODN (SEQ ID NO: 9)5′ T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx  3′ CpG(B)-mutSTAT3dODN(SEQ ID NO: 10) 5′ T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-xxxxx-C*A*T*TTCCCTTAAATC-xxxx-GATTTAAGGGAA*A*T*G-xxxxx  3′CpG(B)-scrambled ODN (SEQ ID NO: 11) 5′T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-xxxxx-A*C*T*CTTGCCAATTAC-xxxx-GTAATTGGCAAG*A*G*T-xxxxx  3′ STAT3dODN alone(SEQ ID NO: 12) 5′ xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx 3′

For uptake studies, various ODN were labeled on the 3′ end (via linker)using Alexa 488 or Cy3.

In Vivo Experiments.

NOD/SCID/IL-2RγKO (NSG) and C57BL/6 mice (6-8 weeks old) were from theNCI (Frederick, Md.) or from the Jackson Laboratory, respectively.TLR9KO mice were originally from provided. Animal care/procedures wereperformed in accordance with established institutional guidance andapproved protocols from the IACUC (COH). NSG or C57BL/6 mice wereinjected into lateral tail vein with 0.5×10⁶MV4-11luc or 1×10⁶ ofCbfb-MYH11/Mpl⁺ AML cells in PBS, respectively. Blood was drawn from theretro-orbital venous sinus to monitor the percentage of circulatingc-Kit⁺/GFP⁺ AML cells. After AML levels in blood exceeded 1% whichcorresponds to 10-20% of bone marrow-residing AML cells (Kuo), NSG andC57BL/6 mice were injected i.v. with various CpG-conjugates (5 mg/kg)every day or every other day, respectively, and euthanized a day afterthe last treatment.

Flow Cytometry and Immunohistochemistry.

Single cell suspensions were prepared by mechanic tissue disruption andcollagenase D/DNase I treatment as described (Kortylewski et al. Nat.Med 2005). The AML cell percentages were determined by GFP and c-Kitexpression. For extracellular staining, cells were incubated withfluorochrome-labeled Annexin V or antibodies to B220, CD3, CD11c, Gr1,F4/80, MHC class II, CD40, CD80, CD86, PDL1, CD3, CD4, CD8 or CD69 afteranti-FcγIII/IIR blocking (eBioscience). For intracellular staining,cells were fixed/permeabilized and stained with antibodies to TLR9(eBioscience), Stat3P or FoxP3 (BD) as described (Kortylewski et al.Nat. Med 2005). Fluorescence data were analyzed on a BD-AccuriC6 FlowCytometer (BD) using FlowJo software (TreeStar). Immunohistochemicalstaining was performed on formalin-fixed/paraffin-embedded bone sections(5 μm) at the Pathology Core (COH).

Quantitative Real-Time PCR and Protein Assays.

Total RNA isolation and cDNA synthesis were carried out as describedpreviously (Zhang et al. Blood 2013). Western blot to detect STAT3,STAT3P and β-actin expression and EMSA assays to detect STAT3 binding toDNA were performed as described (Kortylewski et al. Nat. Biotech. 2009;Zhang et al. Blood 2013). Plasma cytokines were analyzed using Bio-Plexarrays (Bio-Rad) at the Clinical Immunobiology Core (COH).

Statistical Analysis.

One- or two-way analysis of variance plus Bonferroni posttest wereapplied to assess statistical significance of differences betweenmultiple treatment groups or in tumor growth kinetics between treatmentgroups, respectively. Data were analyzed using GraphPad Prism vs 4.0software (GraphPad).

TABLE 2 Compound and component sequences. SEQUENCE (* =phosphorothioate linkage), x = (-(CH₂)₃-)bonded to phosphate groups at both ends except at the terminiwhere terminal phosphates are optionally added and 5′x has an SEQOH terminus and 3′ x has a -C⁶-NH₂ bonded to the final ID NAMEphosphate group, other linkages are phosphodiester. NO.: CpG(A)- 5′G*G*TGCATCGATGCAGG*G*G*G*G-xxxxx- STAT3dODN C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx 3′ (SEQ ID NO: 6) GpC(A)- 5′G*G*TGCATGCATGCAG G*G*G*G*G-xxxxx- STAT3dODNC*A*T*TTCCCGTAAATC-xxxx-GATTT ACGGGAA*A*T*G-xxxxx 3′ (SEQ ID NO: 7)CpG(A)- 5′ G*G*TGCATCGATGCAGG*G*G*G*G-xxxxx- scrambledA*C*T*CTTGCCAATTAC-xxxx-GTAAT ODN TGGCAAG*A*G*T-xxxxx 3′ (SEQ ID NO: 8)CpG(B)- 5′ T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T- STAT3dODNxxxxx-C*A*T*TTCCCGTAAATC-xxxx- GATTTACGGGAA*A*T*G-xxxxx 3′(SEQ ID NO: 9) CpG(B)- 5′ T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-mutSTAT3 xxxxx-C*A*T*TTCCCTTAAATC-xxxx- dODN GATTTAAGGGAA*A*T*G-xxxxx 3′(SEQ ID NO: 10) CpG(B)- 5′ T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-scrambled xxxxx-A*C*T*CTTGCCAATTAC-xxxx- ODN GTAATTGGCAAG*A*G*T-xxxxx 3′(SEQ ID NO: 11) STAT3dODN 5′ xxxxx-C*A*T*TTCCCGTAAATC-xxxx-GATTTACGGGAA*A*T*G-xxxxx 3′ (SEQ ID NO: 12) ODN 15855′-G*G*GGTCAACGTTGAG*G*G*G*G*G-3′ (SEQ ID NO: 13) or5′-G*GGGTCAACGTTGAG*G*G*G*G*G-3′ (SEQ ID NO: 14) ODN 22165′-G*G*GGGACGATCGTCG*G*G*G*G*G-3′ (SEQ ID NO: 15) or5′-G*GGGGACGATCGTCG*G*G*G*G*G-3′ (SEQ ID NO: 16) ODN D195′-G*G*TGCATCGATGCAGG1*G*G*G*G-3′ (SEQ ID NO: 17) or5′-G*GTGCATCGATGCAGG*G*G*G*G-3′ (SEQ ID NO: 18) ODN 23365′-G*G*G*GACGACGTCGTGG*G*G*G*G*G-3′ (SEQ ID NO: 19) or5′-G*G*GGACGACGTCGTGG*G*G*G*G*G-3′ (SEQ ID NO: 20) ODN 16685′-T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*T*G*C*T-3′ (SEQ ID NO: 21) ODN 18265′-T*C*C*A*T*G*A*C*G*T*T*C*C*T*G*A*C*G*T*T-3′ (SEQ ID NO: 22) ODN 20065′- (ODN7909) T*C*G*T*C*G*T*T*T*T*G*T*C*G*T*T*T*T*G*T*C*G* T*T-3′(SEQ ID NO: 23) ODN 2007 5′-T*C*G*T*C*G*T*T*G*T*C*G*T*T*T*T*G*T*C*G*T*T- 3′ (SEQ ID NO: 24) ODN 23955′- T*C*G*T*C*G*T*T*T*T*C*G*G*C*G*C*G*C*G*C*C*G- 3′ (SEQ ID NO: 25)ODN M362 5′- T*C*G*T*C*G*T*C*G*T*T*C*G*A*A*C*G*A*C*G*T*T* G*A*T-3′(SEQ ID NO: 26)

STAT3 is a transcription factor with crucial role in promoting tumorprogression and immune evasion. To achieve STAT3 inhibition specificallyin antigen-presenting cells (APCs), we linked STAT3 decoyoligodeoxynucleotides (STAT3dODN) to a TLR9 ligand, CpG ODN assuccessfully done before for delivery of siRNA molecules. TheCpG-STAT3dODN conjugates are quickly internalized by both human andmouse TLR9-positive target cells such as dendritic cells (DCs),macrophages and B lymphocytes as well as by myeloid leukemia cells.After uptake, CpG-STAT3dODN molecules bind and sequester activated STAT3proteins. The hairpin design and partial phosphorothioation of thebackbone increases half-life of the CpG-STAT3dODN in human serum.Therefore, we assessed the feasibility of using CpG-STAT3dODNs forsystemic administration against disseminated human TLR9+ acute myeloidleukemia (AML). As shown in xenotransplanted MV4-11 AML model repeatedintravenous injections of CpG-STAT3dODN resulted in potent and directantitumor effects effectively eliminating leukemic cells from all testedorgans. The antitumor efficacy of this strategy is enhanced inimmunocompetent mice. Systemic administration of CpG-STAT3dODN inducedregression of the syngeneic mouse Cbfb/MYH11 leukemia within 12 days oftreatment. The potent immune activation was associated with enhancedexpression of antigen-presenting and co-stimulatory molecules not onlyon DCs but also on AML cells. These immunostimulatory effects correlatedwith activation and infiltration of CD8+ T cells into various organswith reduction in regulatory T cell numbers. Our findings highlight thepotential of using CpGSTAT3dODN for the two-pronged TLR9/STAT3-targetedimmunotherapy of human AML.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

What is claimed is:
 1. A compound comprising a toll-like receptor(TLR)-binding nucleic acid substituent conjugated to a signal transducerand activator of transcription (STAT)-binding nucleic acid substituent,wherein said STAT-binding nucleic acid substituent is capable of bindingto a STAT transcription factor.
 2. The compound of claim 1, wherein theTLR-binding nucleic acid substituent is an endosomal TLR-binding nucleicacid substituent.
 3. The compound of claim 1, wherein the TLR-bindingnucleic acid substituent conjugated to a STAT-binding DNA substituent isa nucleic acid sequence comprising SEQ ID NO:21, SEQ ID NO:22, SEQ IDNO:23, or SEQ ID NO:24.
 4. The compound of claim 1, wherein theTLR-binding nucleic acid substituent conjugated to a STAT-binding DNAsubstituent is a nucleic acid sequence comprising SEQ ID NO:23.
 5. Acompound comprising a toll-like receptor 9 (TLR9)-binding DNAsubstituent conjugated to a signal transducer and activator oftranscription 3 (STAT3)-binding DNA substituent, wherein saidSTAT3-binding nucleic acid substituent is capable of binding to a STAT3transcription factor.
 6. The compound of claim 5, wherein theTLR9-binding DNA substituent comprises a CpG motif.
 7. The compound ofclaim 5, wherein the TLR9-binding DNA substituent comprises a Class ACpG DNA sequence, a Class B CpG DNA sequence or a Class C CpG DNAsequence.
 8. The compound of claim 7, wherein the TLR9-binding DNAsubstituent is a Class A CpG DNA sequence.
 9. The compound of claim 7,wherein the TLR9-binding DNA substituent is a Class B CpG DNA sequence.10. The compound of claim 7, wherein the TLR9-binding DNA substituent isa Class C CpG DNA sequence.
 11. The compound of claim 5, wherein theSTAT3-binding DNA substituent comprises a first STAT3-binding DNAsequence covalently bound to a second STAT3-binding DNA sequence by aspacer; and said spacer is a substituted or unsubstituted alkylene,substituted or unsubstituted heteroalkylene, substituted orunsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.
 12. The compound of claim11, wherein the spacer is a substituted or unsubstituted C₁-C₄₀alkylene, substituted or unsubstituted 2 to 40 membered heteroalkylene,substituted or unsubstituted C₃-C₈ cycloalkylene, substituted orunsubstituted 3 to 8 membered heterocycloalkylene, substituted orunsubstituted C₆-C₁₀ arylene, or substituted or unsubstituted 5 to 10membered heteroarylene.
 13. The compound of claim 11, wherein the firstSTAT3-binding DNA sequence and second STAT3-binding DNA sequence form adouble-stranded STAT3-binding DNA sequence.
 14. The compound of claim 5,wherein the STAT3-binding DNA substituent preferentially bindsphosphorylated STAT3 over unphosphorylated STAT3.
 15. The compound ofclaim 5, wherein the STAT3-binding DNA substituent comprises aSTAT3-binding DNA sequence covalently bonded to a terminal moiety; andsaid terminal moiety is a substituted or unsubstituted alkyl,substituted or unsubstituted heteroalkyl, substituted or unsubstitutedcycloalkyl, substituted or unsubstituted heterocycloalkyl, substitutedor unsubstituted aryl, or substituted or unsubstituted heteroaryl. 16.The compound of claim 15, wherein the terminal moiety is anR¹-substituted C₁-C₄₀ alkyl, R¹-substituted 2 to 40 memberedheteroalkyl, R¹-substituted C₃-C₈ cycloalkyl, R¹-substituted 3 to 8membered heterocycloalkyl, R¹-substituted C₆-C₁₀ aryl, or R¹-substituted5 to 10 membered heteroaryl; and R¹ is oxo, oxygen, a detectable moiety,or a therapeutic moiety.
 17. The compound of claim 16, wherein thedetectable moiety is a fluorescent dye, electron-dense reagent, enzyme,biotin, digoxigenin, paramagnetic molecule, paramagnetic nanoparticle,contrast agent, magnetic resonance contrast agent, X-ray contrast agent,Gadolinium, radioisotope, radionuclide, fluorodeoxyglucose, gamma rayemitting radionuclide, positron-emitting radionuclide, biocolloid,microbubble, iodinated contrast agent, barium sulfate, thorium dioxide,gold, gold nanoparticle, gold nanoparticle aggregate, fluorophore,two-photon fluorophore, hapten, protein, or fluorescent moiety.
 18. Thecompound of claim 5, further comprising a linker between theTLR9-binding DNA substituent and the STAT3-binding DNA substituent. 19.The compound of claim 18, wherein the linker is a substituted orunsubstituted alkyl ene, substituted or unsubstituted heteroalkylene,substituted or unsubstituted cycloalkylene, substituted or unsubstitutedheterocycloalkylene, substituted or unsubstituted arylene, orsubstituted or unsubstituted heteroarylene.
 20. The compound of claim 5,further comprising a phosphorothioate linkage.
 21. The compound of claim5, wherein the STAT3-binding DNA substituent is a nucleic acid sequencecomprising SEQ ID NO:12.
 22. The compound of claim 5, wherein theTLR9-binding DNA substituent is a nucleic acid sequence comprising SEQID NO:12, and the STAT3-binding DNA substituent is a nucleic acidsequence comprising SEQ ID NO:23.
 23. The compound of claim 5,comprising nucleic acid SEQ ID NO:6.
 24. A pharmaceutical compositioncomprising a pharmaceutically acceptable excipient and the compound ofclaim 1.